Sulfoximine substituted quinazolines for pharmaceutical compositions

ABSTRACT

The application relates to novel sulfoximine substituted quinazoline derivatives of formula 
                         
wherein Ar, R 1 , R 2  and R 3  are as defined in the description and claims, and their use as MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) kinase inhibitors, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment or amelioration of MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) mediated disorders.

FIELD OF THE INVENTION

This invention relates to sulfoximine substituted quinazolinederivatives and their use as MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a orMNK2b) kinase inhibitors, pharmaceutical compositions containing themand their use in the treatment or amelioration of MNK1 (MNK1a or MNK1b)and/or MNK2 (MNK2a or MNK2b) mediated disorders.

Moreover, the present invention relates to the use of sulfoximinesubstituted quinazoline derivatives of the invention for the productionof pharmaceutical compositions for the prophylaxis and/or treatment ofdiseases which can be influenced by the inhibition of the kinaseactivity of MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) orfurther variants thereof. Particularly, the present invention relates tothe use of sulfoximine substituted quinazoline derivatives of theinvention for the production of pharmaceutical compositions for theprophylaxis and/or therapy of metabolic diseases, such as diabetes,particularly diabetes mellitus type 2, hyperlipidemia and obesity,hematopoietic disorders, neurodegenerative diseases, kidney damage,inflammatory disorders, and cancer and their consecutive complicationsand disorders associated therewith.

BACKGROUND OF THE INVENTION

Metabolic diseases are diseases caused by an abnormal metabolic processand may either be congenital due to an inherited enzyme abnormality oracquired due to a disease of an endocrine organ or failure of ametabolically important organ such as the liver or the pancreas.

The present invention is more particularly directed to the treatmentand/or prophylaxis of in particular metabolic diseases of the lipid andcarbohydrate metabolism and the consecutive complications and disordersassociated therewith.

Lipid disorders cover a group of conditions which cause abnormalities inthe level and metabolism of plasma lipids and lipoproteins. Thus,hyperlipidemias are of particular clinical relevance since theyconstitute an important risk factor for the development ofatherosclerosis and subsequent vascular diseases such as coronary heartdisease.

Diabetes mellitus is defined as a chronic hyperglycemia associated withresulting damages to organs and dysfunctions of metabolic processes.Depending on its etiology, one differentiates between several forms ofdiabetes, which are either due to an absolute (lacking or decreasedinsulin secretion) or to a relative lack of insulin. Diabetes mellitusType I (IDDM, insulin-dependent diabetes mellitus) generally occurs inadolescents under 20 years of age. It is assumed to be of auto-immuneetiology, leading to an insulitis with the subsequent destruction of thebeta cells of the islets of Langerhans which are responsible for theinsulin synthesis. In addition, in latent autoimmune diabetes in adults(LADA; Diabetes Care. 8: 1460-1467, 2001) beta cells are being destroyeddue to autoimmune attack. The amount of insulin produced by theremaining pancreatic islet cells is too low, resulting in elevated bloodglucose levels (hyperglycemia). Diabetes mellitus Type II generallyoccurs at an older age. It is above all associated with a resistance toinsulin in the liver and the skeletal muscles, but also with a defect ofthe islets of Langerhans. High blood glucose levels (and also high bloodlipid levels) in turn lead to an impairment of beta cell function and toan increase in beta cell apoptosis.

Diabetes is a very disabling disease, because today's commonanti-diabetic drugs do not control blood sugar levels well enough tocompletely prevent the occurrence of high and low blood sugar levels.Out of range blood sugar levels are toxic and cause long-termcomplications for example retinopathy, renopathy, neuropathy andperipheral vascular disease. There is also a host of related conditions,such as obesity, hypertension, heart disease and hyperlipidemia, forwhich persons with diabetes are substantially at risk.

Obesity is associated with an increased risk of follow-up diseases suchas cardiovascular diseases, hypertension, diabetes, hyperlipidemia andan increased mortality. Diabetes (insulin resistance) and obesity arepart of the “metabolic syndrome” which is defined as the linkage betweenseveral diseases (also referred to as syndrome X, insulin-resistancesyndrome, or deadly quartet). These often occur in the same patients andare major risk factors for development of diabetes type II andcardiovascular disease. It has been suggested that the control of lipidlevels and glucose levels is required to treat diabetes type II, heartdisease, and other occurrences of metabolic syndrome (see e.g., Diabetes48: 1836-1841, 1999; JAMA 288: 2209-2716, 2002).

In one embodiment of the present invention the compounds andcompositions of the present invention are useful for the treatmentand/or prophylaxis of metabolic diseases of the carbohydrate metabolismand their consecutive complications and disorders such as impairedglucose tolerance, diabetes (preferably diabetes type II), diabeticcomplications such as diabetic gangrene, diabetic arthropathy, diabeticosteopenia, diabetic glomerosclerosis, diabetic nephropathy, diabeticdermopathy, diabetic neuropathy, diabetic cataract and diabeticretinopathy, diabetic maculopathy, diabetic feet syndrome, diabetic comawith or without ketoacidosis, diabetic hyperosmolar coma, hypoglycemiccoma, hyperglycemic coma, diabetic acidosis, diabetic ketoacidosis,intracapillary glomerulonephrosis, Kimmelstiel-Wilson syndrome, diabeticamyotrophy, diabetic autonomic neuropathy, diabetic mononeuropathy,diabetic polyneuropathy, diabetic angiopathies, diabetic peripheralangiopathy, diabetic ulcer, diabetic arthropathy, or obesity indiabetes.

In a further embodiment the compounds and compositions of the presentinvention are useful for the treatment and/or prophylaxis of metabolicdiseases of the lipid metabolism (i.e. lipid disorders) and theirconsecutive complications and disorders such as hypercholesterolemia,familial hypercholesterolemia, Fredrickson's hyperlipoproteinemia,hyperbetalipoproteinemia, hyperlipidemia, low-density-lipoprotein-type[LDL] hyperlipoproteinemia, pure hyperglyceridemia, endogenoushyperglyceridemia, isolated hypercholesterolemia, isolatedhypertroglyceridemia, cardiovascular diseases such as hypertension,ischemia, varicose veins, retinal vein occlusion, atherosclerosis,angina pectoris, myocardial infarction, stenocardia, pulmonaryhypertension, congestive heart failure, glomerulopaty, tubulointestitialdisorders, renal failure, angiostenosis, or cerebrovascular disorders,such as cerebral apoplexy.

In a further embodiment of the present invention the compounds andcompositions of the present invention are useful for the treatmentand/or prophylaxis of hematopoetic disorders and their consecutivecomplications and disorders such as acute myeloid leukemia (AML), MorbusHodgkin, Non-Hodgkin's lymphoma; hematopoetic disease, acutenon-lymphocytic leukemia (ANLL), myeloproliferative disease acutepromyelocytic leukemia (APL), acute myelomonocytic leukemia (AMMoL),multiple myeloma, polycythemia vera, lymphoma, acute lymphocyticleukemia (ALL), chronic lymphocytic leukemia (CCL), Wilm's tumor, orEwing's Sarcoma.

In a further embodiment of the present invention the compounds andcompositions of the present invention are useful for the treatmentand/or prophylaxis of cancer and consecutive complications and disorderssuch as cancer of the upper gastrointestinal tract, pancreaticcarcinoma, breast cancer, colon cancer, ovarian carcinoma, cervixcarcinoma, endometrial cancer, brain tumor, testicular cancer, laryngealcarcinoma, osteocarcinoma, prostatic cancer, retinoblastoma, livercarcinoma, lung cancer, neuroblastoma, renal carcinoma, thyroidcarcinoma, esophageal cancer, soft tissue sarcoma, skin cancer,osteosarcoma, rhabdomyosarcoma, bladder cancer, metastatic cancer,cachexia, or pain.

Certain anti-cancer drugs such as cisplatin are linked to serious sideeffects such as nephrotoxicity or ototoxicity, which can be doselimiting. Activation of MNKs has been linked to these side effects. In afurther embodiment of the present invention, the compounds andcompositions of the present invention are useful for the treatmentand/or prophylaxis of ear or kidney damage, in particular for theprevention or treatment of ear and kidney drug induced damage.

Furthermore, the present invention relates to the use of the compoundsaccording to the invention for the production of pharmaceuticalcompositions for the prophylaxis and/or therapy of cytokine relateddiseases.

Such diseases are i.a. inflammatory diseases, autoimmune diseases,destructive bone disorders, proliferative disorders, infectiousdiseases, neurodegenerative diseases, allergies, or other conditionsassociated with proinflammatory cytokines.

Allergic and inflammatory diseases such as acute or chronicinflammation, chronic inflammatory arthritis, rheumatoid arthritis,psoriasis, COPD, inflammatory bowel disease, asthma and septic shock andtheir consecutive complications and disorders associated therewith.

Inflammatory diseases like rheumatoid arthritis, inflammatory lungdiseases like COPD, inflammatory bowel disease and psoriasis afflict onein three people in the course of their lives. Not only do those diseasesimpose immense health care costs, but also they are often crippling anddebilitating.

Although inflammation is the unifying pathogenic process of theseinflammatory diseases below, the current treatment approach is complexand is generally specific for any one disease. Many of the currenttherapies available today only treat the symptoms of the disease and notthe underlying cause of inflammation.

The compositions of the present invention are useful for the treatmentand/or prophylaxis of inflammatory diseases and consecutivecomplications and disorders. such as chronic or acute inflammation,inflammation of the joints such as chronic inflammatory arthritis,rheumatoid arthritis, psoriatic arthritis, osteoarthritis, juvenilerheumatoid arthritis, Reiter's syndrome, rheumatoid traumatic arthritis,rubella arthritis, acute synovitis and gouty arthritis; inflammatoryskin diseases such as sunburn, psoriasis, erythrodermic psoriasis,pustular psoriasis, eczema, dermatitis, acute or chronic graftformation, atopic dermatitis, contact dermatitis, urticaria andscleroderma; inflammation of the gastrointestinal tract such asinflammatory bowel disease, Crohn's disease and related conditions,ulcerative colitis, colitis, and diverticulitis; nephritis, urethritis,salpingitis, oophoritis, endomyometritis, spondylitis, systemic lupuserythematosus and related disorders, multiple sclerosis, asthma,meningitis, myelitis, encephalomyelitis, encephalitis, phlebitis,thrombophlebitis, respiratory diseases such as asthma, bronchitis,chronic obstructive pulmonary disease (COPD), inflammatory lung diseaseand adult respiratory distress syndrome, and allergic rhinitis;endocarditis, osteomyelitis, rheumatic fever, rheumatic pericarditis,rheumatic endocarditis, rheumatic myocarditis, rheumatic mitral valvedisease, rheumatic aortic valve disease, prostatitis, prostatocystitis,spondoarthropathies ankylosing spondylitis, synovitis, tenosynovotis,myositis, pharyngitis, polymyalgia rheumatica, shoulder tendonitis orbursitis, gout, pseudo gout, vasculitides, inflammatory diseases of thethyroid selected from granulomatous thyroiditis, lymphocyticthyroiditis, invasive fibrous thyroiditis, acute thyroiditis;Hashimoto's thyroiditis, Kawasaki's disease, Raynaud's phenomenon,Sjogren's syndrome, neuroinflammatory disease, sepsis, conjunctivitis,keratitis, iridocyclitis, optic neuritis, otitis, lymphoadenitis,nasopaharingitis, sinusitis, pharyngitis, tonsillitis, laryngitis,epiglottitis, bronchitis, pneumonitis, stomatitis, gingivitis.oesophagitis, gastritis, peritonitis, hepatitis, cholelithiasis,cholecystitis, glomerulonephritis, goodpasture's disease, crescenticglomerulonephritis, pancreatitis, endomyometritis, myometritis,metritis, cervicitis, endocervicitis, exocervicitis, parametritis,tuberculosis, vaginitis, vulvitis, silicosis, sarcoidosis,pneumoconiosis, pyresis, inflammatory polyarthropathies, psoriatricarthropathies, intestinal fibrosis, bronchiectasis and enteropathicarthropathies.

Moreover, cytokines are also believed to be implicated in the productionand development of various cardiovascular and cerebrovascular disorderssuch as congestive heart disease, myocardial infarction, the formationof atherosclerotic plaques, hypertension, platelet aggregation, angina,stroke, Alzheimer's disease, reperfusion injury, vascular injuryincluding restenosis and peripheral vascular disease, and, for example,various disorders of bone metabolism such as osteoporosis (includingsenile and postmenopausal osteoporosis), Paget's disease, bonemetastases, hypercalcaemia, hyperparathyroidism, osteosclerosis,osteoporosis and periodontitis, and the abnormal changes in bonemetabolism which may accompany rheumatoid arthritis and osteoarthritis.

Excessive cytokine production has also been implicated in mediatingcertain complications of bacterial, fungal and/or viral infections suchas endotoxic shock, septic shock and toxic shock syndrome and inmediating certain complications of CNS surgery or injury such asneurotrauma and ischaemic stroke.

Excessive cytokine production has, moreover, been implicated inmediating or exacerbating the development of diseases involvingcartilage or muscle resorption, pulmonary fibrosis, cirrhosis, renalfibrosis, the cachexia found in certain chronic diseases such asmalignant disease and acquired immune deficiency syndrome (AIDS), tumourinvasiveness and tumour metastasis and multiple sclerosis. The treatmentand/or prophylaxis of these diseases are also contemplated by thepresent invention

Additionally, the inventive compositions may be used to treatinflammation associated with autoimmune diseases including, but notlimited to, systemic lupus erythematosis, Addison's disease, autoimmunepolyglandular disease (also known as autoimmune polyglandular syndrome),glomerulonephritis, rheumatoid arthritis scleroderma, chronicthyroiditis, Graves' disease, autoimmune gastritis, diabetes, autoimmunehemolytic anemia, glomerulonephritis, rheumatoid arthritis autoimmuneneutropenia, thrombocytopenia, atopic dermatitis, chronic activehepatitis, myasthenia gravis, multiple sclerosis, inflammatory boweldisease, ulcerative colitis, Crohn's disease, psoriasis, and graft vs.host disease.

In a further embodiment the compositions of the present invention may beused for the treatment and prevention of infectious diseases such assepsis, septic shock, Shigellosis, and Helicobacter pylori and viraldiseases including herpes simplex type 1 (HSV-1), herpes simplex type 2(HSV-2), cytomegalovirus, Epstein-Barr, human immunodeficiency virus(HIV), acute hepatitis infection (including hepatitis A, hepatits B, andhepatitis C), HIV infection and CMV retinitis, AIDS or malignancy,malaria, mycobacterial infection and meningitis. These also includeviral infections, by influenza virus, varicella-zoster virus (VZV),Epstein-Barr virus, human herpesvirus-6 (HHV-6), human herpesvirus-7(HHV-7), human herpesvirus-8 (HHV-8), Poxvirus, Vacciniavirus,Monkeypoxvirus, pseudorabies and rhinotracheitis.

The compositions of the present invention may also be used topically inthe treatment or prophylaxis of topical disease states mediated by orexacerbated by excessive cytokine production, such as inflamed joints,eczema, psoriasis and other inflammatory skin conditions such assunburn; inflammatory eye conditions including conjunctivitis; pyresis,pain and other conditions associated with inflammation.

Periodontal disease has also been implemented in cytokine production,both topically and systemically. Hence, use of compositions of thepresent invention to control the inflammation associated with cytokineproduction in such peroral diseases such as gingivitis and periodontitisis another aspect of the present invention.

Finally, the compositions of the present invention may also be used totreat or prevent neurodegenerative disease selected from Alzheimer'sdisease, Parkinson's disease, amyotrophic lateral sclerosis,Huntington's disease, frontotemporal lobar dementia, spinocerebellarataxia, dementia with Lewy bodies, cerebral ischemia orneurodegenerative disease caused by traumatic injury, glutamateneurotoxicity or hypoxia.

In a preferred embodiment the compositions of the present invention maybe used to treat or prevent a disease selected from chronic or acuteinflammation, chronic inflammatory arthritis, rheumatoid arthritis,psoriasis, COPD, inflammatory bowel disease, septic shock, Crohn'sdisease, ulcerative colitis, multiple sclerosis and asthma.

Protein kinases are important enzymes involved in the regulation of manycellular functions. The LK6-serine/threonine-kinase gene of Drosophilamelanogaster was described as a short-lived kinase which can associatewith microtubules (J. Cell Sci. 1997, 110(2): 209-219). Genetic analysisin the development of the compound eye of Drosophila suggested a role inthe modulation of the RAS signal pathway (Genetics 2000 156(3):1219-1230). The closest human homologues of Drosophila LK6-kinase arethe MAP-kinase interacting kinase 2 (MNK2, e.g. the variants MNK2a andMNK2b) and MAP-kinase interacting kinase 1 (MNK1) and variants thereof.These kinases are mostly localized in the cytoplasm. MNKs arephosphorylated by the p42 MAP kinases Erk1 and Erk2 and the p38-MAPkinases. This phosphorylation is triggered in a response to growthfactors, phorbol esters and oncogenes such as Ras and Mos, and by stresssignaling molecules and cytokines. The phosphorylation of MNK proteinsstimulates their kinase activity towards eukaryotic initiation factor 4E(eIF4E) (EMBO J. 16: 1909-1920, 1997; Mol Cell Biol 19, 1871-1880, 1990;Mol Cell Biol 21, 743-754, 2001). Simultaneous disruption of both, theMNK1 and MNK2 gene in mice diminishes basal and stimulated elF4Ephosphorylation (Mol Cell Biol 24, 6539-6549, 2004). Phosphorylation ofelF4E results in a regulation of the protein translation (Mol Cell Biol22: 5500-5511, 2001).

There are different hypotheses describing the mode of the stimulation ofthe protein translation by MNK proteins. Most publications describe apositive stimulatory effect on the cap-dependent protein translationupon activation of MAP kinase-interacting kinases. Thus, the activationof MNK proteins can lead to an indirect stimulation or regulation of theprotein translation, e.g. by the effect on the cytosolic phospholipase 2alpha (BBA 1488:124-138, 2000).

WO 03/037362 discloses a link between human MNK genes, particularly thevariants of the human MNK2 genes, and diseases which are associated withthe regulation of body weight or thermogenesis. It is postulated thathuman MNK genes, particularly the MNK2 variants are involved in diseasessuch as e.g. metabolic diseases including obesity, eating disorders,cachexia, diabetes mellitus, hypertension, coronary heart disease,hypercholesterolemia, dyslipidemia, osteoarthritis, biliary stones,cancer of the genitals and sleep apnea, and in diseases connected withthe ROS defense, such as e.g. diabetes mellitus and cancer. WO 03/037362moreover discloses the use of nucleic acid sequences of the MAPkinase-interacting kinase (MNK) gene family and amino acid sequencesencoding these and the use of these sequences or of effectors of MNKnucleic acids or polypeptides, particularly MNK inhibitors andactivators in the diagnosis, prophylaxis or therapy of diseasesassociated with the regulation of body weight or thermogenesis.

WO 02/103361 describes the use of kinases 2a and 2b (MNK2a and MNK2b)interacting with the human MAP kinase in assays for the identificationof pharmacologically active ingredients, particularly useful for thetreatment of diabetes mellitus type 2. Moreover, WO 02/103361 disclosesalso the prophylaxis and/or therapy of diseases associated with insulinresistance, by modulation of the expression or the activity of MNK2a orMNK2b. Apart from peptides, peptidomimetics, amino acids, amino acidanalogues, polynucleotides, polynucleotide analogues, nucleotides andnucleotide analogues, 4-hydroxybenzoic acid methyl ester are describedas a substance which binds the human MNK2 protein.

First evidence for a role of MNKs in inflammation was provided bystudies demonstrating activation of MNK1 by proinflammatory stimuli. Thecytokines TNFα and IL-1β trigger the activation of MNK1 in vitro(Fukunaga and Hunter, EMBO J 16(8): 1921-1933, 1997) and induce thephosphorylation of the MNK-specific substrate elF4E in vivo (Ueda etal., Mol Cell Biol 24(15): 6539-6549, 2004). In addition, administrationof lipopolysaccharide (LPS), a potent stimulant of the inflammatoryresponse, induces activation of MNK1 and MNK2 in mice, concomitant witha phosphorylation of their substrate elF4E (Ueda et al., Mol Cell Biol24(15): 6539-6549, 2004).

Furthermore, MNK1 has been shown to be involved in regulating theproduction of proinflammatory cytokines. MNK1 enhances expression of thechemokine RANTES (Nikolcheva et al., J Clin Invest 110, 119-126, 2002).RANTES is a potent chemo-tractant of monocytes, eosinophils, basophilesand, natural killer cells. It activates and induces proliferation of Tlymphocytes, mediates degranulation of basophils and induces therespiratory burst in eosinophils (Conti and DiGioacchino, Allergy AsthmaProc 22(3):133-7, 2001).

WO 2005/003785 and Buxade et al., Immunity 23: 177-189, August 2005 bothdisclose a link between MNKs and the control of TNFα biosynthesis. Theproposed mechanism is mediated by a regulatory AU-rich element (ARE) inthe TNFα mRNA. Buxade et al. demonstrate proteins binding andcontrolling ARE function to be phosphorylated by MNK1 and MNK2.Specifically MNK-mediated phosphorylation of the ARE-binding proteinhnRNP A1 has been suggested to enhance translation of the TNFα mRNA.

TNFα is not the only cytokine regulated by an ARE. Functional AREs arealso found in the transcripts of several interleukins, interferones andchemokines (Khabar, J Interf Cytokine Res 25: 1-10, 2005). TheMNK-mediated phosphorylation of ARE-binding proteins has thus thepotential to control biosynthesis of cytokines in addition to that ofTNFα.

Current evidence demonstrates MNKs as down stream targets ofinflammatory signalling as well as mediators of the inflammatoryresponse. Their involvement in the production of TNFα, RANTES, andpotentially additional cytokines suggests inhibition of MNKs as strategyfor anti-inflammatory therapeutic intervention.

MNK1 and MNK2 (including all splice forms) phosphorylate the translationfactor elF4E on Serine 209. MNK1/2 double knockout mice completely lackphosphorylation on Serine 209, indicating that MNK kinase are the onlykinases able to phosphorylate this site in vivo (Ueda et al., Mol CellBiol. 2004; 24(15):6539-49). elF4E is overexpressed in a wide range ofhuman malignancies, and high elF4E expression is frequently associatedwith more aggressive disease and poor prognosis. Furthermore, elF4E canact as an oncogene when assayed in standard assays for oncogenicactivity (e.g. Ruggero et al., Nat Med. 2004 May; 10(5):484-6). elF4Eexcerts its oncogenic activity by stimulating the translation ofoncogenes such as c-myc and cyclinD1 (Culjkovic et al., J Cell Biol.2006; 175(3):415-26), by increasing the expression of pro-survivalfactors such as MCP-1 (Wendel et al., Genes Dev. 2007; 21(24):3232-7)and by positively regulating pathways of drug resistance (Wendel et al.,Nature 2004; 428(6980):332-7; Graff et el., Cancer Res. 2008;68(3):631-4; De Benedetti and Graff, Oncogene 2004; 23(18):3189-99;Barnhart and Simon, J Clin Invest. 2007; 117(9):2385-8). Suppression ofelF4E expression by antisense oligonucleotides has shown promise inpreclinical experiments with human tumor cells (Graff et al., J ClinInvest. 2007; 117(9):2638-48). It has been shown that phosphorylation onSer209 is strictly required for the oncogenic activity of elF4E in vitroand in vivo (Topisirovic et al., Cancer Res. 2004; 64(23):8639-42;Wendel et al., Genes Dev. 2007; 21(24):3232-7). Thus, inhibition of MNK1and MNK2 is expected to have beneficial effects in human malignancies.

Inhibitors of MNK (referred to as CGP57380 and CGP052088) have beendescribed (cf. Mol. Cell. Biol. 21, 5500, 2001; Mol Cell Biol Res Comm3, 205, 2000; Genomics 69, 63, 2000). CGP052088 is a staurosporinederivative having an IC₅₀ of 70 nM for inhibition of in vitro kinaseactivity of MNK1. CGP57380 is a low molecular weight selective,non-cytotoxic inhibitor of MNK2 (MNK2a or MNK2b) or of MNK1: Theaddition of CGP57380 to cell culture cells, transfected with MNK2 (MNK2aor MNK2b) or MNK1 showed a strong reduction of phosphorylated elF4E.

WO 2007/147874 describes pyridine and pyrazine derivatives as MNK kinaseinhibitors. WO 2007/104053 describes 8-heteroarylpurines as MNK2inhibitors. WO 2006/066937 discloses pyrazolopyrimidine compounds, andWO 2006/136402 discloses certain thienopyrimidine compounds, both usefulas MNK inhibitors.

Aim of the Present Invention

The aim of the present invention is to provide new compounds, inparticular new sulfoximine substituted quinazoline derivatives, whichare MNK1 and/or MNK2 inhibitors.

Another aim of the present invention is to provide new compounds, inparticular new sulfoximine substituted quinazoline derivatives, whichare potent and selective MNK1 and/or MNK2 inhibitors.

A further aim of the present invention is to provide new compounds, inparticular new sulfoximine substituted quinazoline derivatives, whichhave an inhibiting effect on the kinase activity of MNK1 (MNK1a orMNK1b) and/or MNK2 (MNK2a or MNK2b) and/or variants thereof in vitroand/or in vivo and possess suitable pharmacological and pharmacokineticproperties to use them as medicaments.

A further aim of the present invention is to provide effective MNK1and/or MNK2 inhibitors, in particular for the treatment of metabolicdisorders, for example metabolic diseases, inflammatory diseases,cancer, neurodegenerative diseases and their consecutive complicationand disorders.

Still a further aim of the present invention is to provide effectiveMNK1 and/or MNK2 inhibitors, in particular for the treatment ofmetabolic disorders, for example diabetes, particularly diabetesmellitus type 2, dyslipidemia and/or obesity and their consecutivecomplication and disorders.

A further aim of the present invention is to provide methods fortreating a disease or condition mediated by the inhibition of the kinaseactivity of MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) and/orvariants thereof in a patient.

A further aim of the present invention is to provide a pharmaceuticalcomposition comprising at least one compound according to the invention.

A further aim of the present invention is to provide a combination of atleast one compound according to the invention with one or moreadditional therapeutic agents.

A further aim of the present invention is to provide methods for thesynthesis of new compounds, in particular sulfoximine substitutedquinazoline derivatives.

A further aim of the present invention is to provide starting and/orintermediate compounds suitable in methods for the synthesis of newcompounds.

Further aims of the present invention become apparent to the one skilledin the art by the description hereinbefore and in the following and bythe examples.

OBJECT OF THE INVENTION

It has now been found that the compounds according to the inventiondescribed in more detail hereinafter have surprising and particularlyadvantageous properties, in particular as MNK1 and/or MNK2 inhibitors.

The present invention concerns compounds of the general formula I:

wherein

Ar is selected from the group Ar-G1 consisting of:

-   -   wherein X is CH or N;    -   R⁵ is H, halogen or CN, and    -   R⁴ is selected from the group R⁴-G1 consisting of:    -   C₁₋₆-alkyl, C₃₋₇-cycloalkyl, heterocyclyl,        —(CH₂)₁₋₃—C(═O)—NH—(C₁₋₅-alkyl) and        —(CH₂)₁₋₃—C(═O)—N(CH₃)—(C₁₋₅-alkyl),        -   wherein each alkyl or cycloalkyl group of R⁴ is optionally            substituted with one or more F or one CN, OH or CF₃,        -   wherein each heterocyclyl is optionally substituted with one            or more F and/or one OH and —O—(C₁₋₃-alkyl);

R¹ is selected from the group R¹-G1 consisting of halogen, C₁₋₃-alkyland —O—(C₁₋₃-alkyl);

R² is selected from the group R²-G1 consisting of OH, —O—(C₁₋₆-alkyl),—O—(CH₂)₁₋₃—(C₃₋₇-cycloalkyl), —O—(CH₂)₁₋₃—O—(C₁₋₃-alkyl),—O-heterocyclyl and —O—(CH₂)₂₋₄-heterocyclyl,

-   -   wherein in the definition of R², each heterocyclyl is optionally        substituted with one C₁₋₃-alkyl group, and wherein one CH₂ group        of said heterocyclyl group of R² may be replaced with a carbonyl        group;

R³ is selected from the group R³-G1 consisting of:

-   -   wherein R⁶ is C₁₋₂-alkyl;    -   R⁷ is selected from the group consisting of C₁₋₅-alkyl,        C₃₋₇-cycloalkyl and heterocyclyl,        -   wherein the alkyl group of R⁷ is optionally substituted with            one or more F or with one OH or —O—(C₁₋₃-alkyl), and        -   wherein the heterocyclyl group of R⁷ is tetrahydropyranyl;            and    -   or wherein R⁶ and R⁷ together with the sulfur atom to which they        are attached form a 4- to 7-membered saturated or partly        unsaturated heterocycle that may be substituted in any position        not adjacent to the sulfur atom by one or two F, OH or        —O—(C₁₋₃-alkyl) or by one or two C₁₋₃-alkyl and that further to        the sulfur atom may contain one additional heteroatom selected        from the group consisting of O, S and NR^(N),        -   wherein R^(N) is H or C₁₋₃-alkyl,

wherein, if not otherwise specified, each alkyl group in the abovedefinitions is linear or branched and may be substituted with one tothree F;

including any tautomers and stereoisomers thereof,

or a salt thereof

or a solvate or hydrate thereof.

If not specified otherwise, any alkyl moiety mentioned in thisapplication may be straight-chained or branched and may be substitutedwith one to three F.

In a further aspect the present invention relates to processes forpreparing a compound of general formula I and to new intermediatecompounds in these processes.

A further aspect of the invention relates to a salt of the compounds ofgeneral formula I according to this invention, in particular to apharmaceutically acceptable salt thereof.

In a further aspect this invention relates to a pharmaceuticalcomposition, comprising one or more compounds of general formula I orone or more pharmaceutically acceptable salts thereof according to theinvention, optionally together with one or more inert carriers and/ordiluents.

In a further aspect this invention relates to a method for treatingdiseases or conditions which are influenced by the inhibition of thekinase activity of MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b)and/or variants thereof in a patient in need thereof characterized inthat a compound of general formula I or a pharmaceutically acceptablesalt thereof is administered to the patient.

According to another aspect of the invention, there is provided a methodfor treating a metabolic disease or disorder in a patient in needthereof characterized in that a compound of general formula I or apharmaceutically acceptable salt thereof is administered to the patient.

According to another aspect of the invention, there is provided the useof a compound of the general formula I or a pharmaceutically acceptablesalt thereof for the manufacture of a medicament for a therapeuticmethod as described hereinbefore and hereinafter.

According to another aspect of the invention, there is provided acompound of the general formula I or a pharmaceutically acceptable saltthereof for use in a therapeutic method as described hereinbefore andhereinafter.

In a further aspect this invention relates to a method for treating adisease or condition influenced by the inhibition of the kinase activityof MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) and/or variantsthereof in a patient that includes the step of administering to thepatient in need of such treatment a therapeutically effective amount ofa compound of the general formula I or a pharmaceutically acceptablesalt thereof in combination with a therapeutically effective amount ofone or more additional therapeutic agents.

In a further aspect this invention relates to a use of a compound of thegeneral formula I or a pharmaceutically acceptable salt thereof incombination with one or more additional therapeutic agents for thetreatment of diseases or conditions which are influenced by theinhibition of the kinase activity of MNK1 (MNK1a or MNK1b) and/or MNK2(MNK2a or MNK2b) and/or variants thereof.

In a further aspect this invention relates to a pharmaceuticalcomposition which comprises a compound according to general formula I ora pharmaceutically acceptable salt thereof and one or more additionaltherapeutic agents, optionally together with one or more inert carriersand/or diluents.

Other aspects of the invention become apparent to the one skilled in theart from the specification and the experimental part as describedhereinbefore and hereinafter.

DETAILED DESCRIPTION OF THE INVENTION

Unless otherwise stated, the groups, residues and substituents,particularly Ar, R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R^(N) are defined asabove and hereinafter. If residues, substituents, or groups occurseveral times in a compound, they may have the same or differentmeanings. Some preferred meanings of individual groups and substituentsof the compounds according to the invention will be given hereinafter.Any and each of these definitions may be combined with each other.

Ar:

Ar-G1:

According to one embodiment, the group Ar is selected from the groupAr-G1 as defined hereinbefore and hereinafter.

Ar-G2:

According to another embodiment, the group Ar is selected from the groupAr-G2 consisting of:

-   -   wherein X is CH or N;    -   R⁵ is H, halogen or CN; and    -   R⁴ is selected from the group R⁴-G2 consisting of:    -   C₁₋₆-alkyl, C₃₋₇-cycloalkyl, heterocyclyl,        —(CH₂)₁₋₃—C(═O)—NH—(C₁₋₅-alkyl) and        —(CH₂)₁₋₃—C(═O)—N(CH₃)—(C₁₋₅-alkyl);        -   wherein each alkyl or cycloalkyl group of R⁴ is optionally            substituted with one or more F or one CN, OH or CF₃;        -   wherein in the definition of R⁴, each heterocyclyl is            selected from a group consisting of tetrahydrofuranyl,            tetrahydropyranyl and

and is optionally substituted with one or two F and/or OH or—O—(C₁₋₃-alkyl).

Ar-G3:

According to another embodiment, the group Ar is selected from the groupAr-G3 consisting of:

wherein X is CH or N;

R⁵ is H, F, Cl, Br or CN; and

R⁴ is as defined hereinbefore or hereinafter.

Ar-G3a:

According to another embodiment, the group Ar is selected from the groupAr-G3a consisting of:

wherein X is CH or N;

R⁵ is H, F or Cl; and

R⁴ is as defined hereinbefore or hereinafter.

Ar-G4:

According to another embodiment, the group Ar is selected from the groupAr-G4 consisting of:

wherein R⁴ is as defined hereinbefore or hereinafter.

Ar-G4a:

According to another embodiment, the group Ar is selected from the groupAr-G4a consisting of:

wherein R⁴ is

Ar-G5:

According to another embodiment, the group Ar is selected from the groupAr-G5 consisting of:

wherein R⁵ is F or Cl; and

R⁴ is as defined hereinbefore or hereinafter.

Ar-G6:

According to another embodiment, the group Ar is selected from the groupAr-G6 consisting of:

wherein R⁵ is F; and

R⁴ is as defined hereinbefore or hereinafter.

Ar-G7:

According to another embodiment, the group Ar is selected from the groupAr-G7 consisting of:

wherein R⁴ is as defined hereinbefore or hereinafter.

Ar-G7a:

According to another embodiment, the group Ar is selected from the groupAr-G7a consisting of:

wherein R⁴ is isopropyl.

R⁴:

R⁴-G1:

According to one embodiment, the group R⁴ is selected from the groupR⁴-G1 as defined hereinbefore and hereinafter.

R⁴-G2:

According to another embodiment, the group R⁴ is selected from the groupR⁴-G2 consisting of:

C₁₋₆-alkyl, C₃₋₇-cycloalkyl, heterocyclyl,—(CH₂)₁₋₃—C(═O)—NH—(C₁₋₅-alkyl) and —(CH₂)₁₋₃—C(═O)—N(CH₃)—(C₁₋₅-alkyl);

-   -   wherein each alkyl or cycloalkyl group of R⁴ is optionally        substituted with one or more F or one CN, OH or CF₃;    -   wherein in the definition of R⁴, each heterocyclyl is selected        from a group consisting of tetrahydrofuranyl, tetrahydropyranyl        and

and is optionally substituted with F, OH or —O—(C₁₋₃-alkyl).

R⁴-G3:

According to another embodiment, the group R⁴ is selected from the groupR⁴-G3 consisting of:

-   -   1) C₁₋₄-alkyl optionally substituted with one to three F,    -   2) cyclohexyl optionally substituted with OH,    -   3) a heterocyclic group selected from:

-   -   wherein R¹⁰ is H, F, OH or —O—CH₃; and    -   4) —(CH₂)₁₋₃—C(═O)—NH—(C₁₋₄-alkyl),        -   wherein the C₁₋₃-alkyl group linked to the nitrogen atom is            optionally substituted with one to three F.

R⁴-G4:

According to another embodiment, the group R⁴ is selected from the groupR⁴-G4 consisting of:

R¹:

R¹-G1:

According to one embodiment, the group R¹ is selected from the groupR¹-G1 as defined hereinbefore and hereinafter.

R¹-G2:

According to another embodiment, the group R¹ is selected from the groupR¹-G2 consisting of CH₃ and Cl.

R¹-G3:

According to another embodiment, the group R¹ is selected from the groupR¹-G3 consisting of CH₃.

R²:

R²-G1:

According to one embodiment, the group R² is selected from the groupR²-G1 as defined hereinbefore and hereinafter.

R²-G1a:

According to another embodiment, the group R² is selected from the groupR²-G1a consisting of OH, —O—(C₁₋₆-alkyl), —O—(CH₂)₁₋₃—(C₃₋₇-cycloalkyl),—O—(CH₂)₁₋₃—O—(C₁₋₃-alkyl), —O-heterocyclyl and—O—(CH₂)₂₋₄-heterocyclyl,

-   -   wherein each heterocyclyl is selected from a group consisting of        pyrrolidinyl, tetrahydrofuranyl, piperazinyl and morpholinyl,        each optionally substituted with one C₁₋₃-alkyl group, and        wherein one CH₂ group may be replaced with a carbonyl group.

R²-G2:

According to another embodiment, the group R² is selected from the groupR²-G2 consisting of OH, —O—(C₁₋₄-alkyl), —O—CH₂-cyclopropyl,—O—(CH₂)₁₋₃—O—CH₃, —O— tetrahydrofuranyl and —O—(CH₂)₂₋₃-heterocyclyl,

-   -   wherein each heterocyclyl is selected from a group consisting of        pyrrolidinyl, piperazinyl and morpholinyl, each optionally        substituted with one CH₃ group, and wherein one CH₂ group of the        heterocyclyl group may be replaced with a carbonyl group.

R²-G3:

According to another embodiment, the group R² is selected from the groupR²-G3 consisting of OH, —O—(C₁₋₄-alkyl), —O—CH₂-cyclopropyl,—O—(CH₂)₂—O—CH₃, —O-tetrahydrofuranyl and —O—(CH₂)₂₋₃-heterocyclyl,

-   -   wherein each heterocyclyl is selected from a group consisting of        pyrrolidinyl, piperazinyl and morpholinyl, and    -   wherein said piperazinyl group is optionally substituted with        one CH₃ group, and/or    -   wherein one CH₂-group of said piperazinyl group may be replaced        with a carbonyl group.

R²-G4:

According to another embodiment, the group R² is selected from the groupR²-G4 consisting of:

R²-G5:

According to another embodiment, the group R² is selected from the groupR²-G5 consisting of —O—CH₃.

R³:

R³-G1:

According to one embodiment, the group R³ is selected from the groupR³-G1 as defined hereinbefore and hereinafter.

R³-G2:

According to another embodiment, the group R³ is selected from the groupR³-G2 consisting of:

-   -   wherein R⁶ is CH₃;    -   R⁷ is selected from the group consisting of C₁₋₅-alkyl,        cyclopropyl and tetrahydropyranyl,        -   wherein the alkyl group of R⁷ is optionally substituted with            one OH or —O—CH₃, and    -   or wherein R⁶ and R⁷ together with the sulfur atom to which they        are attached form a 4- to 6-membered saturated heterocycle that        may be substituted in any position not adjacent to the sulfur        atom by one OH or —O—CH₃ or by one or two CH₃ and that further        to the sulfur atom may contain one additional heteroatom        selected from the group consisting of O and NH.

R³-G2a:

According to another embodiment, the group R³ is selected from the groupR³-G2a consisting of:

-   -   wherein R⁶ is CH₃;    -   R⁷ is selected from the group consisting of C₁₋₅-alkyl,        cyclopropyl and tetrahydropyranyl,        -   wherein the alkyl group of R⁷ is optionally substituted with            one OH.

Preferably, R⁶ and R⁷ are each methyl.

R³-G2b:

According to another embodiment, the group R³ is selected from the groupR³-G2b consisting of:

-   -   wherein R⁶ and R⁷ together with the sulfur atom to which they        are attached form a 4- to 6-membered saturated heterocycle that        may be substituted in any position not adjacent to the sulfur        atom by one OH or —O—CH₃ and that further to the sulfur atom may        contain one additional heteroatom selected from the group        consisting of O and NH.

R³-G3:

According to another embodiment, the group R³ is selected from the groupR³-G3 consisting of:

wherein R⁶ is CH₃;

R⁷ is C₁₋₄-alkyl, cyclopropyl, —CH₂—CH₂—OH or tetrahydropyranyl; and

Y is CH₂, CH(OH), O or NH.

R³-G4:

According to another embodiment, the group R³ is selected from the groupR³-G4 consisting of:

R³-G5:

According to another embodiment, the group R³ is selected from the groupR³-G5 consisting of:

The following preferred embodiments of compounds of the formula I aredescribed using generic formulae I.1 to I.3, wherein any tautomers andstereoisomers, solvates, hydrates and salts thereof, in particular thepharmaceutically acceptable salts thereof, are encompassed.

wherein the variables R¹, R², R³, R⁴, R⁵ and X are defined ashereinbefore and hereinafter.

Examples of preferred subgeneric embodiments according to the presentinvention are set forth in the following table, wherein each substituentgroup of each embodiment is defined according to the definitions setforth hereinbefore and wherein all other substituents of the formula Iare defined according to the definitions set forth hereinbefore:

Embodiment Ar R⁴ R¹ R² R³ E-1 Ar-G1 R⁴-G1 R¹-G1 R²-G1 R³-G1 E-2 Ar-G2 —R¹-G2 R²-G2 R³-G1 E-3 Ar-G2 — R¹-G2 R²-G2 R³-G2 E-4 Ar-G2 — R¹-G2 R²-G2R³-G2a E-5 Ar-G2 — R¹-G2 R²-G2 R³-G2b E-6 Ar-G2 — R¹-G2 R²-G3 R³-G2a E-7Ar-G2 — R¹-G2 R²-G3 R³-G2b E-8 Ar-G2 — R¹-G2 R²-G2 R³-G3 E-9 Ar-G2 —R¹-G2 R²-G3 R³-G3 E-10 Ar-G2 — R¹-G2 R²-G4 R³-G3 E-11 Ar-G2 — R¹-G2R²-G5 R³-G3 E-12 Ar-G2 — R¹-G2 R²-G2 R³-G4 E-13 Ar-G2 — R¹-G2 R²-G3R³-G4 E-14 Ar-G2 — R¹-G2 R²-G4 R³-G4 E-15 Ar-G2 — R¹-G2 R²-G5 R³-G4 E-16Ar-G2 — R¹-G2 R²-G2 R³-G5 E-17 Ar-G2 — R¹-G2 R²-G3 R³-G5 E-18 Ar-G2 —R¹-G2 R²-G4 R³-G5 E-19 Ar-G2 — R¹-G2 R²-G5 R³-G5 E-20 Ar-G3 R⁴-G2 R¹-G2R²-G2 R³-G2 E-21 Ar-G3 R⁴-G3 R¹-G2 R²-G2 R³-G2 E-22 Ar-G3 R⁴-G4 R¹-G2R²-G2 R³-G2 E-23 Ar-G3a R⁴-G2 R¹-G2 R²-G2 R³-G2 E-24 Ar-G3a R⁴-G3 R¹-G2R²-G2 R³-G2 E-25 Ar-G3a R⁴-G4 R¹-G2 R²-G2 R³-G2 E-26 Ar-G4a — R¹-G3R²-G5 R³-G4 E-27 Ar-G4a — R¹-G3 R²-G5 R³-G5 E-28 Ar-G5 R⁴-G2 R¹-G2 R²-G2R³-G2 E-29 Ar-G5 R⁴-G3 R¹-G2 R²-G2 R³-G2 E-30 Ar-G5 R⁴-G4 R¹-G2 R²-G3R³-G2 E-31 Ar-G5 R⁴-G4 R¹-G3 R²-G4 R³-G2 E-32 Ar-G5 R⁴-G4 R¹-G3 R²-G5R³-G3 E-33 Ar-G6 R⁴-G2 R¹-G2 R²-G2 R³-G2 E-34 Ar-G6 R⁴-G3 R¹-G2 R²-G2R³-G2 E-35 Ar-G6 R⁴-G4 R¹-G2 R²-G3 R³-G2 E-36 Ar-G6 R⁴-G4 R¹-G3 R²-G4R³-G2 E-37 Ar-G6 R⁴-G4 R¹-G3 R²-G5 R³-G3 E-38 Ar-G6 R⁴-G4 R¹-G3 R²-G5R³-G4 E-39 Ar-G6 R⁴-G4 R¹-G3 R²-G5 R³-G5 E-40 Ar-G7 R⁴-G4 R¹-G3 R²-G5R³-G5 E-41 Ar-G7 i-Pr R¹-G3 R²-G5 R³-G5

One embodiment of the invention concerns those compounds of formula (I),wherein

Ar is selected from the group Ar-G2 consisting of:

-   -   wherein X is CH or N;    -   R⁵ is H, halogen or CN; and    -   R⁴ is selected from the group R⁴-G2 consisting of:    -   C₁₋₆-alkyl, C₃₋₇-cycloalkyl, heterocyclyl,        —(CH₂)₁₋₃—C(═O)—NH—(C₁₋₅-alkyl) and        —(CH₂)₁₋₃—C(═O)—N(CH₃)—(C₁₋₅-alkyl);        -   wherein each alkyl or cycloalkyl group of R⁴ is optionally            substituted with one or more F or one ON, OH or CF₃;        -   wherein in the definition of R⁴, each heterocyclyl is            selected from a group consisting of tetrahydrofuranyl,            tetrahydropyranyl and

and is optionally substituted with F, OH or —O—(C₁₋₃-alkyl);

R¹ is selected from the group R¹-G2 consisting of CH₃ and Cl;

R² is selected from the group R²-G2 consisting of:

OH, —O—(C₁₋₄-alkyl), —O—CH₂-cyclopropyl, —O—(CH₂)₁₋₃—O—CH₃,—O-tetrahydrofuranyl and —O—(CH₂)₂₋₃-heterocyclyl,

-   -   wherein each heterocyclyl is selected from a group consisting of        pyrrolidinyl, piperazinyl and morpholinyl, each optionally        substituted with one CH₃ group, and wherein one CH₂ group of the        heterocyclyl group may be replaced with a carbonyl group;

and

R³ is selected from the group R³-G2 consisting of:

-   -   wherein R⁶ is CH₃;    -   R⁷ is selected from the group consisting of C₁₋₅-alkyl,        cyclopropyl and tetrahydropyranyl,        -   wherein the alkyl group of R⁷ is optionally substituted with            one OH or —O—CH₃, and    -   or wherein R⁶ and R⁷ together with the sulfur atom to which they        are attached form a 4- to 6-membered saturated heterocycle that        may be substituted in any position not adjacent to the sulfur        atom by one OH or —O—CH₃ and that further to the sulfur atom may        contain one additional heteroatom selected from the group        consisting of O and NH;

and the pharmaceutically acceptable salts thereof.

Another embodiment of the invention concerns those compounds of formula(I), wherein

Ar is selected from the group Ar-G5 consisting of:

-   -   wherein R⁵ is F or Cl; and    -   R⁴ is selected from the group R⁴-G3 consisting of:    -   1) C₁₋₄-alkyl optionally substituted with one to three F,    -   2) cyclohexyl optionally substituted with OH,    -   3) a heterocyclic group selected from:

-   -   wherein R¹⁰ is H, F, OH or —O—CH₃; and    -   4) —(CH₂)₁₋₃—C(═O)—NH—(C₁₋₄-alkyl),        -   wherein the C₁₋₃-alkyl group linked to the nitrogen atom is            optionally substituted with one to three F;

R¹ is selected from the group R¹-G2 consisting of CH₃ and Cl;

R² is selected from the group R²-G4 consisting of:

and

R³ is selected from the group R³-G3 consisting of:

-   -   wherein R⁶ is CH₃;    -   R⁷ is C₁₋₄-alkyl, cyclopropyl, —CH₂—CH₂—OH or tetrahydropyranyl;        and    -   Y is CH₂, CH(OH), O or NH;

and the pharmaceutically acceptable salts thereof.

Preferred examples for compounds of formula I are:

or a pharmaceutically acceptable salt thereof.

Particularly preferred compounds, including their tautomers andstereoisomers, the salts thereof, or any solvates or hydrates thereof,are described in the experimental section hereinafter.

The compounds according to the invention and their intermediates may beobtained using methods of synthesis which are known to the one skilledin the art and described in the literature of organic synthesis.Preferably the compounds are obtained analogously to the methods ofpreparation explained more fully hereinafter, in particular as describedin the experimental section. In some cases the sequence adopted incarrying out the reaction schemes may be varied. Variants of thesereactions that are known to one skilled in the art but are not describedin detail here may also be used.

The general processes for preparing the compounds according to theinvention will become apparent to a person skilled in the art onstudying the schemes that follow. Starting compounds are commerciallyavailable or may be prepared by methods that are described in theliterature or herein, or may be prepared in an analogous or similarmanner. Before the reaction is carried out any corresponding functionalgroups in the compounds may be protected using conventional protectinggroups. These protecting groups may be cleaved again at a suitable stagewithin the reaction sequence using methods familiar to a person skilledin the art. Typical methods of preparing the compounds of the inventionare described in the experimental section.

The potent inhibitory effect of the compounds of the invention can bedetermined by in vitro enzyme assays as described in the experimentalsection.

The compounds of the present invention may also be made by methods knownin the art including those described below and including variationswithin the skill of the art.

Compounds of the general formula 1-3, wherein X, R³ and R⁴ are aspreviously defined, can be prepared via the process outlined in Scheme 1using a compound of the general formula 1-1, wherein X and R³ are aspreviously defined, with an alcohol of the general formula 1-2, whereinR⁴ is as previously defined, in presence of a base in appropriatesolvents such as THF or DMF at a temperature between 0° C. and 150° C.As a base sodium hydride or lithium hexamethyldisilazane may be used.Hydrogenation of a compound of the general formula 1-3, wherein X, R³and R⁴ are as previously defined, in order to obtain a compound of thegeneral formula 1-4, wherein X, R³ and R⁴ are as previously defined, maybe achieved in the presence of hydrogen and a catalyst such as palladiumor Raney nickel in an appropriate solvent. Hydrogen can be introduced asa gas or stem from a hydrogen source such as ammonium formate.Alternatively, other reducing agents such as Iron, SnCl₂ or TiCl₃ can beutilized to prepare a compound of the general formula 1-4 from 1-3.

As described in Scheme 2 compounds of the general formula 2-3, whereinX, R³ and R⁴ are as previously defined, may be obtained by Mitsunobureaction of a compound with the general formula 2-1, wherein X, R³ areas previously defined, with an alcohol of the general formula 2-2,wherein R⁴ is as previously defined, in the presence of a tertiaryphosphine such as triphenylphosphine and an dialkylazodicarboxylate suchas diethylazodicarboxylate, diisopropylazodicarboxylate ordi-tertbutylazodicarboxylate in a solvent such as THF at temperaturesbetween −10 OC and 80 OC, preferably between 0 OC and 30° C.

4, 5, 6, 7-substituted quinazolines of the general formula 3-4, whereinAr, R¹, R² and R³ are as previously defined, may be prepared as shown inscheme 3. Substituted antranilonitriles of the general formula 3-1,wherein R¹, R² and R³ are as previously defined, may react withN,N-dimethylformamide dimethyl acetal under reflux. The resultingformamidines of the general formula 3-2, wherein R¹, R² and R³ are aspreviously defined, may be condensed with primary aromatic amines of thegeneral formula 3-3, wherein Ar are as previously defined, in aceticacid (J. Med. Chem., 2010, 53 (7), 2892-2901). Dioxane can be used ascosolvent in this reaction. Alternatively, 4-chloro quinazolines of thegeneral formula 3-5 wherein R¹, R² and R³ are as previously defined, maybe condensed with primary aromatic amines of the general formula 3-3,wherein Ar are as previously defined in an inert solvent like dioxane.

The sulphoximine-substituent of the general formula 4-2, wherein R⁵ andR⁶ are as previously defined, may be introduced as shown in Scheme 4 byPd or Cu-catalyzed coupling reactions from the corresponding bromo ortrifluoromethanesulfonate-derivatives of the general formula 4-1 or 4-4,wherein Ar, R¹ and R² are as previously defined.

For the palladium catalyzed coupling one of the following reactionconditions may be used Pd(OAc)₂, BINAP, Cs₂CO₃ in toluene as solvent (J.Org. Chem., 2000, 65 (1), 169-175), or Pd₂dba₃, 2-(di-t-butylphosphino)biphenyl, NaO^(t)Bu in dioxane or DMF as solvent (cf. WO 2008/141843A1).

The substituent R² may be introduced by alkylation of the correspondingphenols of the general formula 5-1 or 5-3, wherein Ar, R¹ and R³ are aspreviously defined, using a suitable base in an inert solvent like K₂CO₃in DMF.

Sulfoximines of the general formula 6-2, wherein R⁵ and R⁶ are aspreviously defined, may be prepared from the corresponding sulfoxides ofthe general formula 6-1, wherein R⁵ and R⁶ are as previously defined, byreaction with o-mesitylenesulfonylhydroxylamine (MSH) in presence of asuitable solvent like dichlormethane.

As shown in scheme 7 sulfoxides of the general formula 7-1, wherein R⁵and R⁶ are as previously defined, may be reacted with trifluoracetamidein the presence of PhI(OAc)₂, Rh₂(OAc)₄, and MgO in a suitable solventlike dichlormethane to form compounds of the general formula 7-2,wherein R⁵ and R⁶ are as previously defined.

Sulfoximines of the general formula 7-3, wherein R⁵ and R⁶ are aspreviously defined, may be prepared by saponification of compounds ofthe general formula 7-2, wherein R⁵ and R⁶ are as previously defined(Org. Lett., 2004, 6 (8), 1305-1307). Alternatively, other suitableprotecting groups and Iron as catalyst can be utilized (Org. Lett.,2006, 8 (11), 2349-2352).

In scheme 8 a general synthesis of sulfoximines of the general formula8-5, wherein R⁵ and R⁶ are as previously defined, is described.

Starting from the thioethers of the general formula 8-1, wherein R⁵ andR⁶ are as previously defined, the corresponding N-cyano sulfilimines ofthe general formula 8-2, wherein R⁵ and R⁶ are as previously defined,may be prepared by reaction with cyanamide in the presence of a baselike NaO^(t)Bu or KO^(t)Bu and NBS or I₂ in a suitable solvent likemethanol. The sulfilimines of the general formula 8-2, wherein R⁵ and R⁶are as previously defined, are oxidized to the N-cyanosulfoximines ofthe general formula 8-3, wherein R⁵ and R⁶ are as previously defined.After removal of the N-cyano group the N-trifluoroacetylsulfoximines ofthe general formula 8-4, wherein R⁵ and R⁶ are as previously defined,may be obtained. After removal of the trifluoroacetyl moiety, theNH-free sulfoximines of the general formula 8-5, wherein R⁵ and R⁶ areas previously defined, can be obtained (Org. Lett., 2007, 9 (19),3809-3811).

Terms and Definitions

Terms not specifically defined herein should be given the meanings thatwould be given to them by one skilled in the art in light of thedisclosure and the context. As used in the specification, however,unless specified to the contrary, the following terms have the meaningindicated and the following conventions are adhered to.

The terms “compound(s) according to this invention”, “compound(s) offormula I”, “compound(s) of the invention” and the like denote thecompounds of the formula I according to the present invention includingtheir tautomers, stereoisomers and mixtures thereof and the saltsthereof, in particular the pharmaceutically acceptable salts thereof,and the solvates and hydrates of such compounds, including the solvatesand hydrates of such tautomers, stereoisomers and salts thereof.

The terms “treatment” and “treating” embraces both preventative, i.e.prophylactic, or therapeutic, i.e. curative and/or palliative,treatment. Thus the terms “treatment” and “treating” comprisetherapeutic treatment of patients having already developed saidcondition, in particular in manifest form. Therapeutic treatment may besymptomatic treatment in order to relieve the symptoms of the specificindication or causal treatment in order to reverse or partially reversethe conditions of the indication or to stop or slow down progression ofthe disease. Thus the compositions and methods of the present inventionmay be used for instance as therapeutic treatment over a period of timeas well as for chronic therapy. In addition the terms “treatment” and“treating” comprise prophylactic treatment, i.e. a treatment of patientsat risk to develop a condition mentioned hereinbefore, thus reducingsaid risk.

When this invention refers to patients requiring treatment, it relatesprimarily to treatment in mammals, in particular humans.

The term “therapeutically effective amount” means an amount of acompound of the present invention that (i) treats or prevents theparticular disease or condition, (ii) attenuates, ameliorates, oreliminates one or more symptoms of the particular disease or condition,or (iii) prevents or delays the onset of one or more symptoms of theparticular disease or condition described herein.

The terms “mediated” or “mediating” or “mediate”, as used herein, unlessotherwise indicated, refers to the (i) treatment, including preventionof the particular disease or condition, (ii) attenuation, amelioration,or elimination of one or more symptoms of the particular disease orcondition, or (iii) prevention or delay of the onset of one or moresymptoms of the particular disease or condition described herein.

The term “substituted” as used herein, means that any one or morehydrogens on the designated atom, radical or moiety is replaced with aselection from the indicated group, provided that the atom's normalvalence is not exceeded, and that the substitution results in anacceptably stable compound.

In the groups, radicals, or moieties defined below, the number of carbonatoms is often specified preceding the group, for example, C₁₋₆-alkylmeans an alkyl group or radical having 1 to 6 carbon atoms. In general,for groups comprising two or more subgroups, the last named subgroup isthe radical attachment point, for example, the substituent“aryl-C₁₋₃-alkyl-” means an aryl group which is bound to aC₁₋₃-alkyl-group, the latter of which is bound to the core or to thegroup to which the substituent is attached.

In case a compound of the present invention is depicted in form of achemical name and as a formula in case of any discrepancy the formulashall prevail.

An asterisk may be used in sub-formulas to indicate the bond which isconnected to the core molecule as defined.

The numeration of the atoms of a substituent starts with the atom whichis closest to the core or the group to which the substituent isattached.

For example, the term “3-carboxypropyl-group” represents the followingsubstituent:

wherein the carboxy group is attached to the third carbon atom of thepropyl group. The terms “1-methylpropyl-”, “2,2-dimethylpropyl-” or“cyclopropylmethyl-” group represent the following groups:

The asterisk may be used in sub-formulas to indicate the bond which isconnected to the core molecule as defined.

In a definition of a group the term “wherein each X, Y and Z group isoptionally substituted with” and the like denotes that each group X,each group Y and each group Z either each as a separate group or each aspart of a composed group may be substituted as defined. For example adefinition “R^(ex) denotes H, C₁₋₃-alkyl, C₃₋₆-cycloalkyl,C₃₋₆-cycloalkyl-C₁₋₃-alkyl or C₁₋₃-alkyl-O—, wherein each alkyl group isoptionally substituted with one or more L^(ex)” or the like means thatin each of the beforementioned groups which comprise the term alkyl,i.e. in each of the groups C₁₋₃-alkyl, C₃₋₆-cycloalkyl-C₁₋₃-alkyl andC₁₋₃-alkyl-O—, the alkyl moiety may be substituted with L^(ex) asdefined.

Unless specifically indicated, throughout the specification and theappended claims, a given chemical formula or name shall encompasstautomers and all stereo-, optical and geometrical isomers (e.g.enantiomers, diastereomers, E/Z isomers etc. . . . ) and racematesthereof as well as mixtures in different proportions of the separateenantiomers, mixtures of diastereomers, or mixtures of any of theforegoing forms where such isomers and enantiomers exist, as well assalts, including pharmaceutically acceptable salts thereof and solvatesthereof such as for instance hydrates including solvates of the freecompounds or solvates of a salt of the compound.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication, andcommensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking pharmaceutically acceptable acid or base salts thereof.

Salts of acids which are useful, for example, for purifying or isolatingthe compounds of the present invention are also part of the invention.

The term halogen generally denotes fluorine, chlorine, bromine andiodine.

The term “C_(1-n)-alkyl”, wherein n is an integer from 2 to n, eitheralone or in combination with another radical denotes an acyclic,saturated, branched or linear hydrocarbon radical with 1 to n C atoms.For example, the term C₁₋₅-alkyl embraces the radicals H₃C—, H₃C—CH₂—,H₃C—CH₂—CH₂—, H₃C—CH(CH₃)—, H₃C—CH₂—CH₂—CH₂—, H₃C—CH₂—CH(CH₃)—,H₃C—CH(CH₃)—CH₂—, H₃C—C(CH₃)₂—, H₃C—CH₂—CH₂—CH₂—CH₂—,H₃C—CH₂—CH₂—CH(CH₃)—, H₃C—CH₂—CH(CH₃)—CH₂—, H₃C—CH(CH₃)—CH₂—CH₂—,H₃C—CH₂—C(CH₃)₂—, H₃C—C(CH₃)₂—CH₂—, H₃C—CH(CH₃)—CH(CH₃)— andH₃C—CH₂—CH(CH₂CH₃)—.

The term “C_(1-n)-alkylene” wherein n is an integer from 2 to n, eitheralone or in combination with another radical, denotes an acyclic,straight-chain or branched divalent alkyl radical containing from 1 to ncarbon atoms. For example, the term C₁₋₄-alkylene includes —(CH₂)—,—(CH₂—CH₂)—, —(CH(CH₃))—, —(CH₂—CH₂—CH₂)—, —(C(CH₃)₂)—, —(CH(CH₂CH₃))—,—(CH(CH₃)—CH₂)—, —(CH₂—CH(CH₃))—, —(CH₂—CH₂—CH₂—CH₂)—,—(CH₂—CH₂—CH(CH₃))—, —(CH(CH₃)—CH₂—CH₂)—, —(CH₂—CH(CH₃)—CH₂)—,—(CH₂—C(CH₃)₂)—, —(C (CH₃)₂—CH₂)—, —(CH(CH₃)—CH(CH₃))—,—(CH₂—CH(CH₂CH₃))—, —(CH(CH₂CH₃)—CH₂)—, —(CH(CH₂CH₂CH₃))—,—(CHCH(CH₃)₂)— and —C(CH₃)(CH₂CH₃)—.

The term “C_(2-n)-alkenyl”, is used for a group as defined in thedefinition for “C_(1-n)-alkyl” with at least two carbon atoms, if atleast two of those carbon atoms of said group are bonded to each otherby a double bond. For example the term C₂₋₃-alkenyl includes —CH═CH₂,—CH═CH—CH₃, —CH₂—CH═CH₂.

The term “C_(2-n)-alkenylene” is used for a group as defined in thedefinition for “C_(1-n)-alkylene” with at least two carbon atoms, if atleast two of those carbon atoms of said group are bonded to each otherby a double bond. For example the term C₂₋₃-alkenylene includes —CH═CH—,—CH═CH—CH₂—, —CH₂—CH═CH—.

The term “C_(2-n)-alkynyl”, is used for a group as defined in thedefinition for “C_(1-n)-alkyl” with at least two carbon atoms, if atleast two of those carbon atoms of said group are bonded to each otherby a triple bond. For example the term C₂₋₃-alkynyl includes —C≡CH,—C≡C—CH₃, —CH₂—C≡CH.

The term “C_(2-n)-alkynylene” is used for a group as defined in thedefinition for “C_(1-n)-alkylene” with at least two carbon atoms, if atleast two of those carbon atoms of said group are bonded to each otherby a triple bond. For example the term C₂₋₃-alkynylene includes —C≡C—,—C≡C—CH₂—, —CH₂—C≡C—.

The term “C_(3-n)-carbocyclyl” as used either alone or in combinationwith another radical, denotes a monocyclic, bicyclic or tricyclic,saturated or unsaturated hydrocarbon radical with 3 to n C atoms. Thehydrocarbon radical is preferably nonaromatic. Preferably the 3 to n Catoms form one or two rings. In case of a bicyclic or tricyclic ringsystem the rings may be attached to each other via a single bond or maybe fused or may form a spirocyclic or bridged ring system. For examplethe term C₃₋₁₀-carbocyclyl includes C₃₋₁₀-cycloalkyl,C₃₋₁₀-cycloalkenyl, octahydropentalenyl, octahydroindenyl,decahydronaphthyl, indanyl, tetrahydronaphthyl. Most preferably the termC_(3-n)-carbocyclyl denotes C_(3-n)-cycloalkyl, in particularC₃₋₇-cycloalkyl.

The term “C_(3-n)-cycloalkyl”, wherein n is an integer 4 to n, eitheralone or in combination with another radical denotes a cyclic,saturated, unbranched hydrocarbon radical with 3 to n C atoms. Thecyclic group may be mono-, bi-, tri- or spirocyclic, most preferablymonocyclic. Examples of such cycloalkyl groups include cyclopropyl,cyclobutyl, cyclo-pentyl, cyclohexyl, cycloheptyl, cyclooctyl,cyclononyl, cyclododecyl, bicyclo[3.2.1.]octyl, spiro[4.5]decyl,norpinyl, norbonyl, norcaryl, adamantyl, etc.

The term bicyclic includes spirocyclic.

The term “C_(3-n)-cycloalkenyl”, wherein n is an integer 3 to n, eitheralone or in combination with another radical, denotes a cyclic,unsaturated but nonaromatic, unbranched hydrocarbon radical with 3 to nC atoms, at least two of which are bonded to each other by a doublebond. For example the term C₃₋₇-cycloalkenyl includes cyclobutenyl,cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl,cycloheptenyl, cycloheptadienyl and cycloheptatrienyl.

The term “aryl” as used herein, either alone or in combination withanother radical, denotes a carbocyclic aromatic monocyclic groupcontaining 6 carbon atoms which may be further fused to a second 5- or6-membered carbocyclic group which may be aromatic, saturated orunsaturated. Aryl includes, but is not limited to, phenyl, indanyl,indenyl, naphthyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl anddihydronaphthyl. More preferably the term “aryl” as used herein, eitheralone or in combination with another radical, denotes phenyl ornaphthyl, most preferably phenyl.

The term “heterocyclyl” means a saturated or unsaturated mono-, bi-,tri- or spirocarbocyclic, preferably mono-, bi- or spirocyclic-ringsystem containing one or more heteroatoms selected from N, O or S(O)_(r)with r=0, 1 or 2, which in addition may have a carbonyl group. Morepreferably the term “heterocyclyl” as used herein, either alone or incombination with another radical, means a saturated or unsaturated, evenmore preferably a saturated mono-, bi- or spirocyclic-ring systemcontaining 1, 2, 3 or 4 heteroatoms selected from N, O or S(O)_(r) withr=0, 1 or 2 which in addition may have a carbonyl group. The term“heterocyclyl” is intended to include all the possible isomeric forms.Examples of such groups include aziridinyl, oxiranyl, azetidinyl,oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl,tetrahydropyranyl, azepanyl, piperazinyl, morpholinyl,tetrahydrofuranonyl, tetrahydropyranonyl, pyrrolidinonyl, piperidinonyl,piperazinonyl and morpholinonyl.

Thus, the term “heterocyclyl” includes the following exemplarystructures which are not depicted as radicals as each form may beattached through a covalent bond to any atom so long as appropriatevalences are maintained:

The term “heteroaryl” means a mono- or polycyclic, preferably mono- orbicyclic ring system containing one or more heteroatoms selected from N,O or S(O)_(r) with r=0, 1 or 2 wherein at least one of the heteroatomsis part of an aromatic ring, and wherein said ring system may have acarbonyl group. More preferably the term “heteroaryl” as used herein,either alone or in combination with another radical, means a mono- orbicyclic ring system containing 1, 2, 3 or 4 heteroatoms selected fromN, O or S(O)_(r) with r=0, 1 or 2 wherein at least one of theheteroatoms is part of an aromatic ring, and wherein said ring systemmay have a carbonyl group. The term “heteroaryl” is intended to includeall the possible isomeric forms.

Thus, the term “heteroaryl” includes the following exemplary structureswhich are not depicted as radicals as each form may be attached througha covalent bond to any atom so long as appropriate valences aremaintained:

Many of the terms given above may be used repeatedly in the definitionof a formula or group and in each case have one of the meanings givenabove, independently of one another.

Pharmacological Activity

The biological activity of compounds was determined by the followingmethods:

A. MNK2a In Vitro Kinase Assay (Assay 1)

Assay Setup:

The inhibition of kinase activity of MNK2a was assessed usingpre-activated GST-MNK2a. The white, 384-well OptiPlate F plates werepurchased from PerkinElmer. The ADP-Glo Kinase Assay (including ultrapure ATP) was purchased from Promega (V9103). Activated MNK2a wasobtained as described in WO2011/104340. The unlabeled elF4E peptide(NH₂-TATKSGSTTKNR-CONH₂), differing from Seq. ID No. 5 of WO 2011/104340by the C-terminal —CONH₂ group, was purchased from Thermo FisherScientific. All other materials were of highest grade commerciallyavailable. Compounds are tested in either serial dilutions or singledose concentrations. The compound stock solutions are 10 mM in 100% DMSOThe serial compound dilutions are prepared in 100% DMSO followed by1:27.3 intermediate dilution in assay buffer. The final DMSOconcentration in assay will be <3%.

In the 384-well plates 3 μl of test compound from the intermediatedilution is mixed with 4 μl of the activated MNK2 enzyme (finalconcentration of 10 nM) and 4 μl of the peptide (final concentration of25 μM)/ultra pure ATP (final concentration of 20 μM), all dissolved inassay buffer. This step is followed by an incubation time of 90 min,then 10 μl of ADP Glo reagent are added, followed by 40 min ofincubation. Then 20 μl of kinase detection reagent are admixed. Theplates are sealed and after an incubation period of 30 min, theluminescence signal is measured in an Envision reader to determine theamount of produced ADP. All incubation steps are performed at roomtemperature.

The assay buffer consists of 20 mM HEPES, 2 mM DTT, 0.01% BSA, 20 mMMgCl₂ and 0.1% Pluronic F-127.

Each assay microtiter plate contains wells with vehicle controls insteadof compound (1% DMSO in water) as reference for the high signal (100%CTL, high signal), and wells containing a potent MNK2 inhibitor (final20 μM, 1% DMSO) as reference for low signal (0% CTL, low signal).

The luminescent signal generated is proportional to the ADPconcentration produced and is correlated with activated MNK2 activity.The analysis of the data is performed by the calculation of thepercentage of ATP consumption of activated MNK2 in the presence of thetest compound compared to the consumption of ATP in the presence ofactivated MNK2 without compound.(RLU(sample)−RLU(low control))*100/(RLU(high value)−RLU(low control))

[RLU=Relative Luminescence Units]

An inhibitor of the MNK2 enzyme will give values between 100% CTL (noinhibition) and 0% CTL (complete inhibition). Values of more than 100%CTL are normally related to compound/sample specific physico-chemicalproperties (e.g. solubility, light absorbance, fluorescence).

IC50 values based on dose response curves are calculated with theAssayExplorer software.

B. MNK1 In Vitro Kinase Assay (Assay 2)

MNK1 Data can be obtained from the MNK1 Z′-LYTE® assay. The MNK1Z′-LYTE® screening protocol and assay conditions are also described onwww.invitrogen.com.

The assay is described as follows:

The Z′-LYTE® biochemical assay employs a fluorescence-based,coupled-enzyme format and is based on the differential sensitivity ofphosphorylated and non-phosphorylated peptides to proteolytic cleavage.The peptide substrate is labeled with two fluorophores—one at eachend—that make up a FRET pair.

In the primary reaction, the kinase transfers the gamma-phosphate of ATPto a single tyrosine, serine or threonine residue in a syntheticFRET-peptide. In the secondary reaction, a site-specific proteaserecognizes and cleaves non-phosphorylated FRET-peptides. Phosphorylationof FRET-peptides suppresses cleavage by the Development Reagent.Cleavage disrupts FRET between the donor (i.e., coumarin) and acceptor(i.e., fluorescein) fluorophores on the FRET-peptide, whereas uncleaved,phosphorylated FRET-peptides maintain FRET. A ratiometric method, whichcalculates the ratio (the Emission Ratio) of donor emission to acceptoremission after excitation of the donor fluorophore at 400 nm, is used toquantitate reaction progress, as shown in the equation below.Emission Ratio=Coumarin Emission(445 nm)/Fluorescein Emission(520 nm)

Assay Setup:

The inhibition of kinase activity of MNK1a was assessed usingpre-activated GST-MNK1a. The 2×MKNK1 (MNK1) mixture is prepared in 50 mMHEPES pH 7.5, 0.01% BRIJ-35, 10 mM MgCl₂, 4 mM MnCl₂, 1 mM EGTA, 2 mMDTT. The final 10 μL Kinase Reaction consists of 13.5-54 ng MKNK1 (MNK1)and 2 μM Ser/Thr 07 in 50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mM MgCl₂, 2mM MnCl₂, 1 mM EGTA, 1 mM DTT. After the 1 hour Kinase Reactionincubation, 5 μL of a 1:32768 dilution of Development Reagent A isadded.

Assay Conditions

Test Compounds:

The Test Compounds are screened in 1% DMSO (final) in the well.

Peptide/Kinase Mixtures:

All Peptide/Kinase Mixtures are diluted to a 2×working concentration inthe MNK1 Kinase Buffer.

ATP Solution:

All ATP Solutions are diluted to a 4×working concentration in KinaseBuffer (50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mM MgCl₂, 1 mM EGTA).

Development Reagent Solution:

The Development Reagent is diluted in Development Buffer

Assay Protocol:

Bar-coded Corning, low volume NBS, 384-well plate (Corning Cat. #3676)

1. 2.5 μL—4×Test Compound

2. 5 μL—2×Peptide/Kinase Mixture

3. 2.5 μL—4×ATP Solution

4. 30-second plate shake

5. 60-minute Kinase Reaction incubation at room temperature

6. 5 μL—Development Reagent Solution

7. 30-second plate shake

8. 60-minute Development Reaction incubation at room temperature

9. Read on fluorescence plate reader and analyze the data

Data Analysis

The following equations are used for each set of data points:

Correction for Background Fluorescence: FI_(Sample)−FI_(TCFI Ctl)Emission Ratio (using values corrected for backgroundfluorescence):Coumarin Emission (445 nm)/Fluorescein Emission (520 nm)

% Phosphorylation (% Phos):1−((Emission Ratio×F _(100%))−C _(100%))/((C _(0%) −C _(100%))+[EmissionRatio×(F _(100%) −F _(0%))])*100

% Inhibition:1−(% Phos_(Sample)/% Phos_(0% Inhibition Ctl))*100FI=Fluorescence IntensityC_(100%)=Average Coumarin emission signal of the 100% Phos. ControlC_(0%)=Average Coumarin emission signal of the 0% Phos. ControlF_(100%)=Average Fluorescein emission signal of the 100% Phos. ControlF_(0%)=Average Fluorescein emission signal of the 0% Phos. Control

Graphing Software

SelectScreen® Kinase Profiling Service uses XLfit from IDBS. The doseresponse curve is curve fit to model number 205 (sigmoidal dose-responsemodel). If the bottom of the curve does not fit between −20% & 20%inhibition, it is set to 0% inhibition. If the top of the curve does notfit between 70% and 130% inhibition, it is set to 100% inhibition.

The activity of MNK proteins can be assayed also by other in vitrokinase assay formats. For example, suitable kinase assays have beendescribed in the literature in Knauf et al., Mol Cell Biol. 2001 August;21(16):5500-11 or in Scheper et al., Mol Cell Biol. 2001 February;21(3):743-54. In general, MNK kinase assays can be performed such that aMNK substrate such as a protein or a peptide, which may or may notinclude modifications as further described below, or others arephosphorylated by MNK proteins having enzymatic activity in vitro. Theactivity of a candidate agent can then be determined via its ability todecrease the enzymatic activity of the MNK protein. The kinase activitymay be detected by change of the chemical, physical or immunologicalproperties of the substrate due to phosphorylation.

In one example, the kinase substrate may have features, designed orendogenous, to facilitate its binding or detection in order to generatea signal that is suitable for the analysis of the substratesphosphorylation status. These features may be, but are not limited to, abiotin molecule or derivative thereof, a glutathione-S-transferasemoiety, a moiety of six or more consecutive histidine residues, an aminoacid sequence or hapten to function as an epitope tag, a fluorochrome,an enzyme or enzyme fragment. The kinase substrate may be linked tothese or other features with a molecular spacer arm to avoid sterichindrance.

In another example the kinase substrate may be labelled with afluorophore. The binding of the reagent to the labelled substrate insolution may be followed by the technique of fluorescence polarizationas it is described in the literature. In a variation of this example, afluorescent tracer molecule may compete with the substrate for theanalyte to detect kinase activity by a technique which is known to thoseskilled in the art as indirect fluorescence polarization.

In yet another example, radioactive gamma-ATP is used in the kinasereaction, and the effect of the test agent on the incorporation ofradioactive phosphate in the test substrate is determined relative tocontrol conditions.

It has been shown that the compounds of the invention exhibit low IC₅₀values in in vitro biological screening assays for inhibition of MNK 1and/or MNK 2 kinase activity. The following table contains the testresults for exemplary compounds.

C. Biological Data

TABLE 1 Biological data of the compounds of the present invention asobtained in assay 1. Mnk2 # IC₅₀ [nM] 1.01 5.5 nM 1.02 2.4 nM 1.03 1.6nM 1.04 2.4 nM 2.01 2.5 nM 2.02 12.6 nM  2.03 1.2 nM 2.04 1.2 nM 2.052.5 nM 2.06 1.2 nM 2.07 2.7 nM 2.08 1.4 nM 2.09 1.8 nM 2.10 3.3 nM 2.111.9 nM 2.12 2.3 nM 2.13 1.7 nM 2.14 3.7 nM 2.15 1.4 nM 2.16 3.5 nM 2.172.1 nM 2.18 1.3 nM 2.19 2.8 nM 2.20 3.8 nM 2.21 1.9 nM 2.22 2.5 nM 2.23 2 nM 2.24 4.4 nM 2.25 0.8 nM 2.26  1 nM 2.27 3.9 nM 2.28 2.2 nM 2.292.6 nM 2.30 1.3 nM 2.31 2.1 nM 2.32 4.1 nM 2.33 1.6 nM 2.34  2 nM 2.351.5 nM 2.36 1.8 nM 2.37 4.1 nM 2.38  2 nM 2.39 2.4 nM 2.40 1.3 nM 2.411.6 nM 2.42 1.2 nM 2.43 2.3 nM 2.44 1.4 nM 2.45 1.7 nM 2.46  2 nM 2.471.4 nM 2.48 1.3 nM 2.49 2.3 nM 2.50  2 nM 2.51 6.9 nM 2.52 2.3 nM 2.531.6 nM 2.54 1.6 nM 2.55 1.6 nM 2.56 2.7 nM 2.57 1.1 nM 2.58 2.4 nM 2.591.4 nM 3.01 3.3 nM 3.02 2.6 nM 3.03 6.5 nM 3.04 2.1 nM

TABLE 2 Biological data of selected compounds of the present inventionas obtained in assay 2. Mnk1 # IC₅₀ [nM] 1.01 162 nM  1.02 51 nM 1.03 54nM 2.02 25 nM 2.06 18 nM 2.09 14 nM 2.11 56 nM 2.15 42 nM 2.20 57 nM2.21 33 nM 2.25 18 nM 2.26 64 nM 2.27 87 nM 2.32 65 nM 2.35 74 nM 2.3615 nM 2.38 55 nM 2.39 66 nM 2.40 16 nM 2.42 52 nM 2.44 41 nM 2.45 17 nM2.46 37 nM 2.47 28 nM 2.48 22 nM 2.50 44 nM 2.57 22 nM 2.58 38 nM 3.01180 nM  3.02 113 nM  3.03 282 nM  3.04 118 nM 

TABLE 3 % Inhibition of MNK1 at a compound concentration of 1 μM asobtained in assay 2 Mnk1 # % Inh 2.01 103 2.03 105 2.04 105 2.05 1062.08 107 2.10 96 2.12 95 2.13 103 2.14 98 2.16 102 2.17 94 2.18 95 2.19102 2.22 98 2.23 105 2.24 100 2.29 96 2.30 105 2.31 96 2.33 106 2.34 942.37 88 2.41 106 2.43 97 2.49 95 2.51 77 2.52 100 2.53 105 2.54 91 2.55104 2.56 97 2.59 108

Method of Treatment

In view of their ability to inhibit the activity of the MNK1 (MNK1a orMNK1b) and/or MNK2 (MNK2a or MNK2b) kinase, the compounds of generalformula I according to the invention, including the corresponding saltsthereof, are theoretically suitable for the treatment of all thosediseases or conditions which may be affected or which are mediated bythe inhibition of the MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b)kinase.

Accordingly, the present invention relates to a compound of generalformula I as a medicament.

Furthermore, the present invention relates to the use of a compound ofgeneral formula I or a pharmaceutical composition according to thisinvention for the treatment and/or prevention of diseases or conditionswhich are mediated by the inhibition of the MNK1 (MNK1a or MNK1b) and/orMNK2 (MNK2a or MNK2b) kinase in a patient, preferably in a human.

In yet another aspect the present invention relates to a method fortreating a disease or condition mediated by the inhibition of the MNK1(MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) kinase in a mammal thatincludes the step of administering to a patient, preferably a human, inneed of such treatment a therapeutically effective amount of a compoundor a pharmaceutical composition of the present invention.

Diseases and conditions mediated by inhibitors of the inhibition of theMNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) kinase embracemetabolic diseases or conditions.

The present invention is directed to compounds which are useful in thetreatment and/or prevention of a disease, disorder and/or conditionwherein the inhibition of the activity of the MNK1 (MNK1a or MNK1b)and/or MNK2 (MNK2a or MNK2b) kinase is of therapeutic benefit, includingbut not limited to the treatment of metabolic diseases, such as obesity,eating disorders, cachexia, diabetes mellitus, metabolic syndrome,hypertension, coronary heart diseases, hypercholesterolemia,dyslipidemia, osteoarthritis, biliary stones and/or sleep apnea anddiseases related to reactive oxygen compounds (ROS defense) such asdiabetes mellitus, neurodegenerative diseases and cancer.

The pharmaceutical compositions of the invention are particularly usefulfor prophylaxis and treatment of obesity, diabetes mellitus and othermetabolic diseases of the carbohydrate and lipid metabolism as statedabove, in particular diabetes mellitus and obesity.

Thus, in a more preferred embodiment of this invention the use of acompound of the invention for the production of a pharmaceuticalcomposition for the prophylaxis or therapy of metabolic diseases isprovided.

In yet a further aspect of the invention the use of a compound of theinvention for the production of a pharmaceutical composition fortreating or preventing a cytokine mediated disorder such as aninflammatory disease is provided.

The pharmaceutical compositions of the invention are thus useful for theprophylaxis or therapy of inflammatory diseases, in particular chronicor acute inflammation, chronic inflammatory arthritis, rheumatoidarthritis, psoriatic arthritis, osteoarthritis, juvenile rheumatoidarthritis, gouty arthritis; psoriasis, erythrodermic psoriasis, pustularpsoriasis, inflammatory bowel disease, Crohn's disease and relatedconditions, ulcerative colitis, colitis, diverticulitis, nephritis,urethritis, salpingitis, oophoritis, endomyometritis, spondylitis,systemic lupus erythematosus and related disorders, multiple sclerosis,asthma, meningitis, myelitis, encephalomyelitis, encephalitis,phlebitis, thrombophlebitis, chronic obstructive disease (COPD),inflammatory lung disease, allergic rhinitis, endocarditis,osteomyelitis, rheumatic fever, rheumatic pericarditis, rheumaticendocarditis, rheumatic myocarditis, rheumatic mitral valve disease,rheumatic aortic valve disease, prostatitis, prostatocystitis,spondoarthropathies ankylosing spondylitis, synovitis, tenosynovotis,myositis, pharyngitis, polymyalgia rheumatica, shoulder tendonitis orbursitis, gout, pseudo gout, vasculitides, inflammatory diseases of thethyroid selected from granulomatous thyroiditis, lymphocyticthyroiditis, invasive fibrous thyroiditis, acute thyroiditis;Hashimoto's thyroiditis, Kawasaki's disease, Raynaud's phenomenon,Sjogren's syndrome, neuroinflammatory disease, sepsis, conjubctivitis,keratitis, iridocyclitis, optic neuritis, otitis, lymphoadenitis,nasopaharingitis, sinusitis, pharyngitis, tonsillitis, laryngitis,epiglottitis, bronchitis, pneumonitis, stomatitis, gingivitis,oesophagitis, gastritis, peritonitis, hepatitis, cholelithiasis,cholecystitis, glomerulonephritis, goodpasture's disease, crescenticglomerulonephritis, pancreatitis, dermatitis, endomyometritis,myometritis, metritis, cervicitis, endocervicitis, exocervicitis,parametritis, tuberculosis, vaginitis, vulvitis, silicosis, sarcoidosis,pneumoconiosis, inflammatory polyarthropathies, psoriatricarthropathies, intestinal fibrosis, bronchiectasis and enteropathicarthropathies.

As already stated above, the compositions of the present invention areparticularly useful for treating or preventing a disease selected fromchronic or acute inflammation, chronic inflammatory arthritis,rheumatoid arthritis, psoriasis, COPD, inflammatory bowel disease,septic shock, Crohn's disease, ulcerative colitis, multiple sclerosisand asthma.

Thus, in a more preferred embodiment of this invention the use of acompound according to the invention for the production of apharmaceutical composition for the prophylaxis or therapy ofinflammatory diseases selected from chronic or acute inflammation,chronic inflammatory arthritis, rheumatoid arthritis, psoriasis, COPD,inflammatory bowel disease, septic shock Crohn's disease, ulcerativecolitis, multiple sclerosis and asthma is provided.

In yet a further aspect of the invention the use of a compound of theinvention for the production of a pharmaceutical composition fortreating or preventing cancer, viral diseases or neurodegenerativediseases is provided.

In a further aspect of the invention the use of a compound of thepresent invention for the production of a pharmaceutical composition forinhibiting the activity of the kinase activity of MNK1 (MNK1a or MNK1b)and/or MNK2 (MNK2a, MNK2b) or further variants thereof is provided, inparticular for the prophylaxis or therapy of metabolic diseases,hematopoietic disorders, cancer and their consecutive complications anddisorders. Whereby the prophylaxis and therapy of metabolic diseases ofthe carbohydrate and/or lipid metabolism is preferred.

For the purpose of the present invention, a therapeutically effectivedosage will generally be from about 1 to 2000 mg/day, preferably fromabout 10 to about 1000 mg/day, and most preferably from about 10 toabout 500 mg/day, which may be administered in one or multiple doses.

It will be appreciated, however, that specific dose level of thecompounds of the invention for any particular patient will depend on avariety of factors such as age, sex, body weight, general healthcondition, diet, individual response of the patient to be treated timeof administration, severity of the disease to be treated, the activityof particular compound applied, dosage form, mode of application andconcomitant medication. The therapeutically effective amount for a givensituation will readily be determined by routine experimentation and iswithin the skills and judgment of the ordinary clinician or physician.In any case the compound or composition will be administered at dosagesand in a manner which allows a therapeutically effective amount to bedelivered based upon patient's unique condition.

It will be appreciated by the person of ordinary skill in the art thatthe compounds of the invention and the additional therapeutic agent maybe formulated in one single dosage form, or may be present in separatedosage forms and may be either administered concomitantly (i.e. at thesame time) or sequentially.

The pharmaceutical compositions of the present invention may be in anyform suitable for the intended method of administration.

The compounds, compositions, including any combinations with one or moreadditional therapeutic agents, according to the invention may beadministered by oral, transdermal, inhalative, parenteral or sublingualroute. Of the possible methods of administration, oral or intravenousadministration is preferred.

Pharmaceutical Compositions

Suitable preparations for administering the compounds of formula I,optionally in combination with one or more further therapeutic agents,will be apparent to those with ordinary skill in the art and include forexample tablets, pills, capsules, suppositories, lozenges, troches,solutions, syrups, elixirs, sachets, injectables, inhalatives andpowders etc. Oral formulations, particularly solid forms such as e.g.tablets or capsules are preferred. The content of the pharmaceuticallyactive compound(s) is advantageously in the range from 0.1 to 90 wt.-%,for example from 1 to 70 wt.-% of the composition as a whole.

Suitable tablets may be obtained, for example, by mixing one or morecompounds according to formula I with known excipients, for exampleinert diluents, carriers, disintegrants, adjuvants, surfactants, bindersand/or lubricants. The tablets may also consist of several layers. Theparticular excipients, carriers and/or diluents that are suitable forthe desired preparations will be familiar to a person skilled in the arton the basis of his specialist knowledge. The preferred ones are thosethat are suitable for the particular formulation and method ofadministration that are desired. The preparations or formulationsaccording to the invention may be prepared using methods known per sethat are familiar to one skilled in the art, such as for example bymixing or combining at least one compound of formula I according to theinvention, or a pharmaceutically acceptable salt of such a compound andone or more excipients, carriers and/or diluents.

Combination Therapy

The compounds of the invention may further be combined with one or more,preferably one additional therapeutic agent. According to one embodimentthe additional therapeutic agent is selected from the group oftherapeutic agents useful in the treatment of diseases or conditionsdescribed hereinbefore, in particular associated with metabolic diseasesor conditions such as for example diabetes mellitus, obesity, diabeticcomplications, hypertension, hyperlipidemia. Additional therapeuticagents which are suitable for such combinations include in particularthose which for example potentiate the therapeutic effect of one or moreactive substances with respect to one of the indications mentionedand/or which allow the dosage of one or more active substances to bereduced.

Other active substances which are suitable for such combinationsinclude, for example, antidiabetics like insulin, long and short actinginsulin analogues, sulfonylureas, biguanides, DPP-IV inhibitors, SGLT2inhibitors, 11ß-HSD inhibitors, glucokinase activators, AMPK activators,GIp-1 receptor agonists, GIP receptor agonists, DGAT inhibitors,PPARgamma agonists, PPARdelta agonists, and other antidiabetics derivedfrom thiazolidinediones, lipid lowering agents such as statines,fibrates, ion exchange resins nicotinic acid derivatives, or HMG-CoAreductase inhibitors, cardiovascular therapeutics such as nitrates,antihypertensiva such as β-blockers, ACE inhibitors, Ca-channelblockers, angiotensin II receptor antagonists, diuretics, thrombocyteaggregation inhibitors, or antineoplastic agents such as alkaloids,alkylating agents, antibiotics, or antimetabolites, or anti-obesityagents. Further preferred compositions are compositions wherein theadditional therapeutic agent is selected from a histamine antagonist, abradikinin antagonist, serotonin antagonist, leukotriene, ananti-asthmatic, an NSAID, an antipyretic, a corticosteroid, anantibiotic, an analgetic, a uricosuric agent, chemotherapeutic agent, ananti gout agent, a bronchodilator, a cyclooxygenase-2 inhibitor, asteroid, a 5-lipoxygenase inhibitor, an immunosuppressive agent, aleukotriene antagonist, a cytostatic agent, an antineoplastic agent, amTor inhibitor, a Tyrosine kinase inhibitor, antibodies or fragmentsthereof against cytokines and soluble parts (fragments) of cytokinereceptors.

More particularly preferred are compounds such as human NPH insulin,human lente or ultralente insulin, insulin Lispro, insulin Aspart,insulin Glulisine, insulin detemir or insulin Glargine, metformin,phenformin, acarbose, miglitol, voglibose, pioglitazone, rosiglizatone,rivoglitazone, aleglitazar, alogliptin, saxagliptin, sitagliptin,vildagliptin, exenatide, liraglutide, albiglutide, pramlintide,carbutamide, chlorpropamide, glibenclamide (glyburide), gliclazide,glimepiride, glipizide, gliquidone, tolazamide, tolbutamide, atenolol,bisoprolol, metoprolol, esmolol, celiprolol, talinolol, oxprenolol,pindolol, propanolol, bupropanolol, penbutolol, mepindolol, sotalol,certeolol, nadolol, carvedilol, nifedipin, nitrendipin, amlodipin,nicardipin, nisoldipin, diltiazem, enalapril, verapamil, gallopamil,quinapril, captopril, lisinopril, benazepril, ramipril, peridopril,fosinopril, trandolapril, irbesatan, losartan, valsartan, telmisartan,eprosartan, olmesartan, hydrochlorothiazide, piretanid, chlorotalidone,mefruside, furosemide, bendroflumethiazid, triamterene, dehydralazine,acetylsalicylic acid, tirofiban-HCl, dipyramidol, triclopidin,iloprost-trometanol, eptifibatide, clopidogrel, piratecam, abciximab,trapidil, simvastatine, bezafibrate, fenofibrate, gemfibrozil,etofyllin, clofibrate, etofibrate, fluvastatine, lovastatine,pravastatin, colestyramide, colestipol-HCl, xantinol nicotinat, inositolnicotinat, acipimox, nebivolol, glycerolnitrate, isosorbide mononitrate,isosorbide dinitrate, pentaerythrityl tetranitrate, indapamide,cilazepril, urapidil, eprosartan, nilvadipin, metoprolol, doxazosin,molsidormin, moxaverin, acebutolol, prazosine, trapidil, clonidine,vinca alkaloids and analogues such as vinblastin, vincristin, vindesin,vinorelbin, podophyllotoxine derivatives, etoposid, teniposid,alkylating agents, nitroso ureas, N-lost analogues, cycloplonphamid,estamustin, melphalan, ifosfamid, mitoxantron, idarubicin, doxorubicin,bleomycin, mitomycin, dactinomycin, daptomycin, docetaxel, paclitaxel,carboplatin, cisplatin, oxaliplatin, BBR3464, satraplatin, busulfan,treosulfan, procarbazine, dacarbazine, temozolomide, chlorambucil,chlormethine, cyclophosphamide, ifosfamide, melphalan, bendamustine,uramustine, ThioTEPA, camptothecin, topotecan, irinotecan, rubitecan,etoposide, teniposide, cetuximab, panitumumab, trastuzumab, rituximab,tositumomab, alemtuzumab, bevacizumab, gemtuzumab, aminolevulinic acid,methyl aminolevulinate, porfimer sodium, verteporfin, axitinib,bosutinib, cediranib, dasatinib, erlotinib, gefitinib, imatinib,lapatinib, lestaurtinib, nilotinib, semaxanib, sorafenib, sunitinib,vandetanib, retinoids (alitretinoin, tretinoin), altretamine, amsacrine,anagrelide, arsenic trioxide, asparaginase (pegaspargase), bexarotene,bortezomib, denileukin diftitox, estramustine, ixabepilone, masoprocol,mitotane, testolactone, tipifarnib, abetimus, deforolimus, everolimus,gusperimus, pimecrolimus, sirolimus, tacrolimus, temsirolimus,antimetabolites such as cytarabin, fluorouracil, fluoroarabin,gemcitabin, tioguanin, capecitabin, combinations such asadriamycin/daunorubicin, cytosine arabinosid/cytarabine, 4-HC, or otherphosphamides.

Other particularly preferred compounds are compounds such as clemastine,diphenhydramine, dimenhydrinate, promethazine, cetirizine, astemizole,levocabastine, loratidine, terfenadine, acetylsalicylic acid, sodoumsalicylate, salsalate, diflunisal, salicylsalicylic acid, mesalazine,sulfasalazine, osalazine, acetaminophen, indomethacin, sulindac,etodolac, tolmetin, ketorolac, bethamethason, budesonide, chromoglycinicacid, dimeticone, simeticone, domperidone, metoclopramid, acemetacine,oxaceprol, ibuprofen, naproxen, ketoprofen, flubriprofen, fenoprofen,oxaprozin, mefenamic acid, meclofenamic acid, pheylbutazone,oxyphenbutazone, azapropazone, nimesulide, metamizole, leflunamide,eforicoxib, lonazolac, misoprostol, paracetamol, aceclofenac,valdecoxib, parecoxib, celecoxib, propyphenazon, codein, oxapozin,dapson, prednisone, prednisolon, triamcinolone, dexibuprofen,dexamethasone, flunisolide, albuterol, salmeterol, terbutalin,theophylline, caffeine, naproxen, glucosamine sulfate, etanercept,ketoprofen, adalimumab, hyaluronic acid, indometacine, proglumetacinedimaleate, hydroxychloroquine, chloroquine, infliximab, etofenamate,auranofin, gold, [²²⁴Ra]radium chloride, tiaprofenic acid,dexketoprofen(trometamol), cloprednol, sodium aurothiomalateaurothioglucose, colchicine, allopurinol, probenecid, sulfinpyrazone,benzbromarone, carbamazepine, lornoxicam, fluorcortolon, diclofenac,efalizumab, idarubicin, doxorubicin, bleomycin, mitomycin, dactinomycin,daptomycin, cytarabin, fluorouracil, fluoroarabin, gemcitabin,tioguanin, capecitabin, adriamydin/daunorubicin, cytosinearabinosid/cytarabine, 4-HC, or other phosphamides, penicillamine, ahyaluronic acid preparation, arteparon, glucosamine, MTX, solublefragments of the TNF-receptor (such as etanercept (Enbrel)) andantibodies against TNF (such as infliximab (Remicade), natalizumab(Tysabri) and adalimumab (Humira)).

EXAMPLES

Preliminary Remarks:

The hereinafter described compounds have been characterized throughtheir characteristic mass after ionisation in a mass-spectrometer andtheir retention time on an analytical HPLC.

LIST OF ABBREVIATIONS

-   ACN acetonitrile-   AcOH acetic acid-   aq. aqueous-   BOC tert-butoxy-carbonyl--   ° C. degree celsius-   dba dibenzylideneacetone-   DCM dichloromethane-   DMAP 4-dimethylaminopyridine-   DMF N,N-dimethylformamide-   DMPU 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone-   ESI-MS electrospray ionisation mass spectrometry-   EtOAc ethyl acetate-   EtOH ethanol-   FC flash-cromatography, SiO₂ is used if no further details given-   h hour-   HPLC high performance liquid chromatography-   L liter-   MeOH methanol-   min minute-   ml milliliter-   MS mass spectrum-   μW reaction was performed in a microwave-   n.d. not determined-   NH4OH solution of NH₃ in water-   NMP N-methyl-2-pyrrolidinon-   psi pound per square inch-   RT room temperature (about 20° C.)-   R_(t) retention time-   TF/TFA trifluoroacetic acid-   THF tetrahydrofuran-   Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene-   XtalFluor-E (diethylamino)difluorosulfonium tetrafluoroborate

HPLC Methods

HPLC-A: Agilent 1200 with DA- and MS-detector, XBridge C18_3.0×30 mm,2.5 μm (Waters), 60° C.

Time [min] % Sol [H₂O 0.1% TFA] % Sol [Acetonitrile] Flow [ml/min] 0.097.0 3.0 2.2 0.2 97.0 3.0 2.2 1.2 0.0 100.0 2.2 1.25 0.0 100.0 3.0 1.40.0 100.0 3.0

HPLC-G: Waters 1525 with DA- and MS-detector, Sunfire C18_4.6×30 mm, 2.5μm (Waters), 60° C.

Time [min] % Sol [H₂O 0.1% TFA] % Sol [Methanol] Flow [ml/min] 0.0 95.05.0 4.0 0.05 95.0 5.0 3.0 2.05 0.0 100.0 3.0 2.1 0.0 100.0 4.5 2.4 0.0100.0 4.5

HPLC-H: Agilent 1200 with DA- and MS-detector, XBridge C18_3×30 mm, 2.5μm (Waters), 60° C.

Time [min] % Sol [H₂O 0.1% TFA] % Sol [Methanol] Flow [ml/min] 0.0 95.05.0 2.2 0.3 95.0 5.0 2.2 1.5 0.0 100.0 2.2 1.55 0.0 100.0 2.9 1.65 0.0100.0 2.9

HPLC-K: Waters Acquity with 3100 MS, XBridge BEH C18_3.0×30 mm, 1.7 μm(Waters), 60° C.

Time [min] % Sol [H₂O 0.1% NH₄OH] % Sol [Acetonitrile] Flow [ml/min] 0.095.0 5.0 1.5 0.7 0.1 99.9 1.5 0.8 0.1 99.9 1.5 0.81 95.0 5.0 1.5 1.195.0 5.0 1.5

HPLC-M: Agilent 1200 with DA- and MS-detector, XBridge C18_3.0×30 mm,2.5 μm (Waters), 60° C.

Time [min] % Sol [H₂O 0.1% NH₄OH] % Sol [Acetonitrile] Flow [ml/min] 0.097.0 3.0 2.2 0.2 97.0 3.0 2.2 1.2 0.0 100.0 2.2 1.25 0.0 100.0 3.0 1.40.0 100.0 3.0

HPLC-N: Waters Acquity with DA- and MS-detector and CTC autosampler,XBridge C18_3.0×30 mm, 2.5 μm (Waters), 60° C.

Time [min] % Sol [H₂O 0.1% NH₄OH] % Sol [Acetonitrile] Flow [ml/min] 0.098.0 2.0 2.0 1.2 0.0 100.0 2.0 1.4 0.0 100.0 2.0

HPLC-Q: Waters Acquity with 3100 MS, Sunfire C18_2.1×50 mm, 2.5 μm(Waters), 60° C.

Time % Sol [Acetonitrile [min] % Sol [H₂O 0.1% TFA] 0.08% TFA] Flow[ml/min] 0.0 95.0 5.0 1.5 0.75 0.0 100.0 1.5 0.85 0.0 100.0 1.5

HPLC-T: Waters Acquity with 3100 MS, Sunfire C18_3.0×30 mm, 2.5 μm(Waters), 60° C.

Time [min] % Sol [H₂O 0.1% NH₄OH] % Sol [Acetonitrile] Flow [ml/min] 0.095.0 5.0 1.5 1.3 1.0 99.0 1.5 1.5 0.1 99.9 1.5 1.6 95.0 5.0 1.5

HPLC-U: Waters Acquity with DA- and MS-detector and CTC autosampler,Sunfire C18_2.1×30 mm, 2.5 μm (Waters), 60° C.

Time [min] % Sol [H₂O 0.1% TFA] % Sol [Acetonitrile] Flow [ml/min] 0.099.0 1.0 1.5 0.02 99.0 1.0 1.5 1.0 0.0 100.0 1.5 1.1 0.0 100.0 1.5

HPLC-V: Agilent 1100 with DA-detector, XBridge C18_3.0×30 mm, 2.5 μm(Waters), 6000

Time [min] % Sol [H₂O 0.1% NH₄OH] % Sol [Acetonitrile] Flow [ml/min] 0.098.0 2.0 2.0 1.2 0.0 100.0 2.0 1.4 0.0 100.0 2.0

HPLC-W: XBridge BEH C18_2.1×30 mm, 1.7 μm (Waters), 60° C.

Time [min] % Sol [H₂O, 0.1% TFA] % Sol [Acetonitrile] Flow [ml/min] 0.099 1 1.6 0.02 99 1 1.6 1.00 0 100 1.6 1.10 0 100 1.6

HPLC-X: Sunfire C18_3.0×30 mm, 2.5 μm (Waters), 60° C.

Time [min] % Sol [H₂O 0.1% TFA] % Sol [Acetonitrile] Flow [ml/min] 0.098.0 2.0 2.0 1.2 0.0 100.0 2.0 1.4 0.0 100.0 2.0

HPLC-Z: Sunfire C18_3.0×30 mm, 2.5 μm (Waters), 60° C.

Time [min] % Sol [H₂O 0.1% TFA] % Sol [Acetonitrile] Flow [ml/min] 0.099.0 1.0 2.0 0.9 0.0 100.0 2.0 1.1 0.0 100.0 2.0

Preparation of Intermediates:

Intermediate I.1:

Step 1:

To a mixture of 96 g (489 mmol) methyl4-methyl-1,3-benzodioxole-5-carboxylate (can be obtained according toWO2010117425) in Ac₂O 35 ml (489 mmol) 65% HNO₃ was added at 0° C., thenstirred for 2 h at this temperature. The mixture was added to ice-watersolution dropwise with stirring. Then DCM was added. The aq. phase wasextracted with DCM, organic layer was separated, and concentrated togive crude product which was tirtuated with MTBE and filtered yieldingmethyl 4-methyl-6-nitro-1,3-benzodioxole-5-carboxylate.

Yield: 61 g (47%), ESI-MS: m/z=240 (M+H)⁺

Step 2:

To a mixture of 36.1 g (151 mmol) methyl4-methyl-6-nitro-1,3-benzodioxole-5-carboxylate and MeOH, 84 ml of a 30%solution of NaOMe in MeOH (454 mmol) was added and the reaction mixtureheated to reflux for 4 h, then cooled to RT and stirred over night. Thencooled to 0° C. and 132 ml of a 4 M HCl solution (528 mmol) were addedfollowed by 120 ml water. The mixture was extracted with iPrOAc, theorganic layer was separated, and concentrated giving rise to methyl4-hydroxy-3-methoxy-2-methyl-6-nitro-benzoate.

Yield: 38 g (95% Purity), ESI-MS: m/z=259 (M+NH₄)

Step 3:

3.8 g 10% Pd/C are added to 38 g (95% purity, 150 mmol) methyl4-hydroxy-3-methoxy-2-methyl-6-nitro-benzoate in MeOH. The reactionmixture is stirred at RT for 6 h under a hydrogen atmosphere (126 psi).The catalyst is filtered off and the filtrate is evaporated and purifiedby FC yielding methyl 6-amino-4-hydroxy-3-methoxy-2-methyl-benzoate.

Yield: 28 g (89%), ESI-MS: m/z=212 (M+H)⁺

Step 4:

A mixture of 28 g (132 mmol) methyl6-amino-4-hydroxy-3-methoxy-2-methyl-benzoate 41.5 g (399 mmol)formamidine acetate and MeOH is heated to reflux for 2.5 h. Then themixture is cooled to 0° C. and the precipitate is filtered off andwashed with methanol giving rise to7-hydroxy-6-methoxy-5-methyl-3H-quinazolin-4-one.

Yield: 27 g (90% Purity), ESI-MS: m/z=207 (M+H)⁺

Step 5:

A mixture of 27 g (90% purity, 108 mmol)7-hydroxy-6-methoxy-5-methyl-3H-quinazolin-4-one 76.4 ml (808 mmol) Ac₂Oand 17.4 ml (216 mmol) Pyridine is heated to 100° C. for 1 h. Then themixture is cooled to RT and water is added dropwise the precipitate isfiltered off, washed with water and dried furnishing(6-methoxy-5-methyl-4-oxo-3H-quinazolin-7-yl) acetate.

Yield: 20 g (75%), ESI-MS: m/z=249 (M+H)⁺

Step 6:

A mixture of 1.2 g (4.8 mmol)(6-methoxy-5-methyl-4-oxo-3H-quinazolin-7-yl) acetate 0.5 ml (5.8 mmol)POCl₃, 2.0 ml (11.60 mmol) DIPEA and DCM is heated to reflux for 22 h.Additional 0.5 ml (5.8 mmol) POCl₃ and 2.0 ml (11.60 mmol) DIPEA areadded and the mixture is refluxed for 20 h. The reaction mixture isconcentrated and DCM and saturated NaHCO₃ solution is added. The organicphase is separated, dried, diluted with EtOAc and passed through a plugof silica yielding (4-chloro-6-methoxy-5-methyl-quinazolin-7-yl)acetate.

Yield: 1.0 g (78%), ESI-MS: m/z=267/269 (M+H)⁺, R_(t)(HPLC): 0.92 min(HPLC-A)

Intermediate I.2:

Is prepared in similar fashion as Intermediate 1.1 from methyl4-chloro-1,3-benzodioxole-5-carboxylate

ESI-MS: m/z=287/289 (M+H)⁺, R_(t)(HPLC): 0.96 min (HPLC-A)

Intermediate II.1:

Step 1:

A mixture of 5.0 g (26.0 mmol) 3-methoxy-2-methyl-6-nitro-benzonitrile(can be obtained according to U.S. Pat. No. 6,211,196) and TFA is cooledto 0° C. and 3.8 g (13.2 mmol) dibromoisocyanuric acid is added in smallportions. The reaction mixture is warmed to RT, stirred over night anddiluted with ice water. The precipitate was filtered and dried givingrise to 4-bromo-3-methoxy-2-methyl-6-nitro-benzonitrile

Yield: 5.4 g (76%), ESI-MS: m/z=288 M+NH₄ ⁺, R_(t)(HPLC): 0.61 min(HPLC-G)

Step 2:

A mixture of 2.0 g (7.4 mmol)4-bromo-3-methoxy-2-methyl-6-nitro-benzonitrile and acetone is cooled to0° C. and 47 ml (74.4 mmol) 20% TiCl₃ solution in water is slowly addedfollowed by 75 ml (300 mmol) 4 M NH₄OAc solution in water. The reactionmixture is stirred at 0° C. for 3 h then warmed to RT. Diluted withEtOAc and water, the aqueous phase is separated and extracted withEtOAc. The organic phases are pooled, washed with brine, dried withMgSO₄ filtered and evaporated. Ether is added to the residual and theprecipitate is filtered off. The filtrate is evaporated and purified viaFC yielding 6-amino-4-bromo-3-methoxy-2-methyl-benzonitrile Yield: 1.3 g(73%), ESI-MS: m/z=241 M+H⁺, R_(t)(HPLC): 0.54 min (HPLC-G)

Step 3:

A mixture of 3.7 g (15.2 mmol)6-amino-4-bromo-3-methoxy-2-methyl-benzonitrile And 37 mlN,N-dimethylformamide dimethyl acetal is stirred at 120° C. for 3 h. Thereaction mixture is evaporated and purified via FC resultingN′-(5-bromo-2-cyano-4-methoxy-3-methyl-phenyl)-N, N-dimethyl-formamidineYield: 3.8 g (84%), ESI-MS: m/z=296 M+H⁺, R_(t)(HPLC): 0.36 min (HPLC-G)

Intermediate II.2:

To a mixture of 3.0 g (10.1 mmol)N′-(5-bromo-2-cyano-4-methoxy-3-methyl-phenyl)-N,N-dimethyl-formamidine(intermediate II.1) and DCM 30 ml (30 mmol) BBr₃ solution 1 M in DCM isadded. The reaction mixture is stirred at RT for 20 h and diluted withsaturated NaHCO₃ solution. The organic phase is separated, dried overMgSO₄ and evaporated, giving rise toN′-(5-bromo-2-cyano-4-hydroxy-3-methyl-phenyl)-N,N-dimethyl-formamidine.

Yield: 2.0 g (70%), ESI-MS: m/z=282 M+H⁺, R_(t)(HPLC): 0.28 min (HPLC-G)

Intermediate II.3:

To a mixture of 1.9 g (6.7 mmol)N′-(5-bromo-2-cyano-4-hydroxy-3-methyl-phenyl)-N,N-dimethyl-formamidine(intermediate II.2), 1.7 ml (12.1 mmol) triethylamine and DCM 0.6 ml(8.2 mmol) acetyl chloride is added and the reaction mixture is stirredat RT for 5.5 h. Additional 0.26 ml (1.8 mmol) triethylamine and 0.1 ml(1.4 mmol) acetyl chloride are added and the reaction mixture is stirredat RT for 1 h and diluted with water. The organic phase is separated andevaporated, giving rise to[6-bromo-3-cyano-4-[(E)-dimethylaminomethyleneamino]-2-methyl-phenyl]acetate.

Yield: 2.0 g (92%), ESI-MS: m/z=324 M+H⁺, R_(t)(HPLC): 0.38 min (HPLC-G)

Intermediate II.4:

A mixture of 0.2 g (0.57 mmol) intermediate II.2, 0.1 g (0.73 mmol)4-(3-Chloro-propyl)-morpholine, 0.2 g (1.23 mmol) K₂CO₃ and acetonitrileis heated to 80° C. in a sealed tube for 6 h. After cooling to RT thesolvent is evaporated and DCM and water are added. The organic phase isseparated, dried, filtered and evaporated.

Yield: 0.2 g (Purity 70%), ESI-MS: m/z=409 M+H⁺, R_(t)(HPLC): 0.98 min(HPLC-M)

Intermediate II.5:

Step 1:

A mixture of 0.2 g (0.71 mmol) intermediate II.2, 0.1 g (0.92 mmol)1-Bromo-3-chloro-propane, 0.2 g (1.56 mmol) K₂CO₃ and acetonitrile isheated to 80° C. in a sealed tube for 5 h. After cooling to RT thesolvent is evaporated and DCM and water are added. The organic phase isseparated, dried, filtered and evaporated.

Yield: 0.2 g (Purity 90%), ESI-MS: m/z=358/360 M+H⁺, R_(t)(HPLC): 1.12min (HPLC-M)

Step 2:

A mixture of 0.2 g (0.50 mmol) intermediate II.5 step 1, 70 mg (0.61mmol) 1-Methylpiperazin-2-one, 90 mg (0.65 mmol) K₂CO₃ and acetonitrileis heated to 80° C. in a pressure tube for 3.5 h. After cooling to RTthe solvent is evaporated and DCM and water are added. The organic phaseis separated, dried, filtered and evaporated.

Yield: 0.1 g (Yield 59%), ESI-MS: m/z=436 M+H⁺, R_(t)(HPLC): 0.25 min(HPLC-W)

Step 3:

A mixture of 130 mg (0.30 mmol) intermediate II.5 step 2, 42 mg (0.45mmol) dimethylsulphoximine, 36 mg (0.12 mmol) 2-(di-t-butylphosphino)biphenyl, 27 mg (0.03 mmol) Pd₂dba₃ and 66 mg (0.69 mmol) sodiumtert-butoxide and dioxane and heated to 80° C. for 2.25 h in a sealedtube After cooling to RT the solvent is evaporated and DCM and water areadded. The organic phase is separated, dried, filtered and evaporated.

The crude product is purified by FC.

Yield: 60 mg (Yield 45%), ESI-MS: m/z=449 M+H⁺, R_(t)(HPLC): 0.77 min(HPLC-M)

Intermediate II.6

Is prepared in similar fashion as Intermediate II.5 using pyrrolidine asnucleophile ESI-MS: m/z=406 M+H⁺, R_(t)(HPLC): 0.96 min (HPLC-M)

Intermediate II.7:

Step 1:

A mixture of 0.2 g (0.64 mmol) intermediate II.2, 0.1 g (0.94 mmolBromo-ethane, 0.2 g (1.45 mmol) K₂CO₃ and acetonitrile is heated to 80°C. in a sealed tube for 5 h. After cooling to RT the solvent isevaporated and DCM and water are added. The organic phase is separated,dried, filtered and evaporated.

Yield: 0.2 g (Purity 85%), ESI-MS: m/z=310 M+H⁺, R_(t)(HPLC): 1.07 min(HPLC-M)

Step 2:

A mixture of 180 mg (0.58 mmol) intermediate II.7 step 1, 81 mg (0.87mmol) dimethylsulphoximine, 70 mg (0.24 mmol) 2-(di-t-butylphosphino)biphenyl, 53 mg (0.06 mmol) Pd₂dba₃ and 130 mg (1.35 mmol) sodiumtert-butoxide and dioxane and heated to 80° C. for 2.75 h in a sealedtube After cooling to RT the solvent is evaporated and DCM and water areadded. The organic phase is separated, dried, filtered and evaporated.The crude product is purified by FC.

Yield: 97 mg (Yield 59%), ESI-MS: m/z=323 M+H⁺, R_(t)(HPLC): 0.83 min(HPLC-M)

Intermediate II.8:

Is prepared in similar fashion as Intermediate II.7 using4-(2-Chloro-ethyl)-morpholine as electrophile

ESI-MS: m/z=408 M+H⁺, R_(t)(HPLC): 0.80 min (HPLC-M)

Intermediate III.1:

2.2 ml (20.0 mmol) 2,4-difluoro-1-nitro-benzene and 2.9 g (20.0 mmol)1,4:3,6-dianhydro-D-mannitol in 70 ml THF are cooled to −5° C. 20 ml(20.0 mml) 1M LiHMDS in THF are added dropwise and the reaction mixtureis allowed to warm to RT and stirred over night. 1M HCl is added and themixture is extracted with EtOAc. The organic phases are pooled andwashed with water, dried and evaporated. The residue is purified by FC.

Yield: 2.7 g (47%), ESI-MS: m/z=286 (M+H)⁺, R_(t)(HPLC): 0.80 min(HPLC-H)

Intermediate III.2:

To 0.9 g (3.0 mmol)(3R,3aR,6R,6aR)-6-(5-fluoro-2-nitro-phenoxy)-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol(III.1), 0.1 g (0.3 mmol) tetrabutylammonium iodide and 1.3 ml (7.8mmol) of a 6 mol/l aqueous NaOH solution in 15 ml DCM 0.3 ml (3.6 mmol)dimethyl sulfate are added dropwise and the mixture is stirred at RT for24 h. Additional 1.3 ml (7.8 mmol) of a aqueous 6 mol/l NaOH solutionand 0.3 ml (3.6 mml) dimethyl sulfate are added and the mixture isstirred at RT over night. The reaction mixture is washed with water,dried and evaporated. The residue is purified by FC.

Yield: 0.8 g (85%), ESI-MS: m/z=300 (M+H)⁺, R_(t)(HPLC): 0.90 min(HPLC-H)

Intermediate III.3:

2.9 g (5.0 mmol)(3S,3aR,6R,6aR)-6-(5-fluoro-2-nitro-phenoxy)-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol(prepared as described for III.1 from 2,4-difluoro-1-nitro-benzene and1,4:3,6-dianhydro-D-sorbitol) and 1.2 g (15.0 mmol) pyridine in DCM arecooled to 0° C. 2.0 ml (12.0 mml) trifluoromethanesulfonic anhydride isadded dropwise and after 1 h the reaction mixture is allowed to warm toRT and stirred over night. The reaction mixture is washed with water,10% citric acid, water, dried and evaporated.

Yield: 4.0 g (96%), ESI-MS: m/z=418 (M+H)⁺, R_(t)(HPLC): 0.95 min(HPLC-A)

Intermediate III.4:

To 4.0 g (9.6 mmol)[(3R,3aR,6S,6aS)-3-(5-fluoro-2-nitro-phenoxy)-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]trifluoromethanesulfonate (intermediate III.3) in acetonitrile 1.1 g(28.8 mmol) sodium borohydride are added. The reaction mixture isstirred at RT for 10 days. The reaction mixture is evaporated, taken upin ice water, carefully acidified with aqueous 4 mol/l HCl and extractedwith EtOAc. The organic phases are pooled, washed with water, dried andevaporated. The residue is purified by FC.

Yield: 1.6 g (62%), ESI-MS: m/z=270 (M+H)⁺, R_(t)(HPLC): 0.75 min(HPLC-A)

Intermediate III.5:

3.7 g (8.9 mmol)[(3R,3aR,6R,6aS)-3-(5-fluoro-2-nitro-phenoxy)-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]trifluoromethanesulfonate (prepared as described for III.3 from III.1)in 53.2 ml of a 1M solution of tetrabutylammonium flouride in THF (53.2mmol) is stirred at RT for 3 h. Water and DCM are added and the organiclayer is separated, washed with water, dried and evaporated. The residuewas purified by FC.

Yield: 2.3 g (89%), ESI-MS: m/z=288 (M+H)⁺, R_(t)(HPLC): 0.80 min(HPLC-A)

Intermediate III.6:

Step 1:

A mixture of 2,4-difluoronitrobenzene (2.81 ml; 25.7 mmol),(3S,4S)-4-(tert-butyl-dimethyl-silanyloxy)-tetrahydro-furan-3-ol(WO2013/55577; diol starting material: Synthesis, 1992, pp. 951-953),7.00 g; 25.6 mmol THF (100 ml), and sodium hydride (60% dispersion inmineral oil; 1.03 g; 25.7 mmol) is stirred at RT over night. DCM isadded and the mixture is extracted with water. The organic layer isseparated, dried with magnesium sulphate, filtered and evaporated. Theresidue is purified by FC (DCM).

Yield: 6.07 g (66%), ESI-MS: m/z=358 (M+H)⁺

Step 2:

A mixture of(3S,4S)-tert-Butyl-[4-(5-fluoro-2-nitro-phenoxy)-tetrahydro-furan-3-yloxy]dimethyl-silane(6.07 g; 12.7 mmol) and AcOH/water/THF (3:1:1, 50 ml) is stirred at RTover night. Volatiles are evaporated, the residue is taken up in waterand extracted with DCM. The organic layer is separated, dried withmagnesium sulphate, filtered and evaporated. The residue is purified byFC (DCM/MeOH 96:4).

Yield: 2.95 g (95%), ESI-MS: m/z=244 (M+H)⁺, Specific rotation: [α]_(D)²⁰ (MeOH)=+21°

Intermediate III.7:

Step 1:

To 8.4 g (34.5 mmol) methyl (2R)-2-(5-fluoro-2-nitro-phenoxy)propanoate(prepared as described for III.1 from from 2,4-difluoro-1-nitro-benzeneand (R)-2-Hydroxy-propionic acid methyl ester) in THF and 69.1 ml (69.1mmol) 1 N NaOH in water are added and the mixture is stirred at RT for30 min. The reaction mixture is cooled to 0° C. and neutralized with 1 MHCl, concentrated and extracted with EtOAc. The organic phases arepooled dried and evaporated. The residual is titruated with PE andfiltered giving rise to (2R)-2-(5-fluoro-2-nitro-phenoxy)propanoic acid.

Yield: 7.2 g (91%), ESI-MS: m/z=230 (M+H)⁺, R_(t)(HPLC): 0.81 min(HPLC-A)

Step 2:

To a mixture of 1.5 g (6.55 mmol)(2R)-2-(5-fluoro-2-nitro-phenoxy)propanoic acid, 0.78 g (7.86 mmol),2.13 g (16.4 mmol) diisopropylethylamine and DMF 2.7 g (7.2 mmol) HATUare added and the reaction mixture is stirred at RT for 1 h andevaporated. The crude product is purified by FC.

Yield: 1.7 g (84%), ESI-MS: m/z=311 (M+H)⁺, R_(t)(HPLC): 0.94 min(HPLC-A)

Intermediate III.8:

A mixture of 1.6 g (10 mmol) 5-Fluoro-nitrophenol 3.1 ml (12 mmol)tert-Butyldiphenylcholorsilane and pyridine is stirred for 3 h at RT.The solvent is evaporated and water and EtOAc are added. The organicphase is separated, dried and evaporated and the residual is purified byFC.

Yield: 4 g (quantitative), ESI-MS: m/z=413 (M+NH₄)⁺, R_(t)(HPLC): 1.20min (HPLC-A)

Intermediate III.8:Intermediate III.9:

Is prepared in similar manner as intermediate III.8 using5-Chloro-nitrophenol ESI-MS: m/z=429 (M+NH₄)⁺, R_(t)(HPLC): 1.32 min(HPLC-M)

Intermediate IV.1:

0.3 g 10% Pd/C are added to 2.6 g (9.1 mmol) III.1 in 70 ml EtOAc. Thereaction mixture is stirred at RT for 5 h under a hydrogen atmosphere(50 psi). The catalyst is filtered off and the filtrate is evaporated.

Yield: 2.3 g (99%), ESI-MS: m/z=256 (M+H)⁺, R_(t)(HPLC): 0.34 min(HPLC-H)

Intermediate IV.2:

Is prepared in a similar manner as intermediate IV.1 from2,4-difluoro-1-nitro-benzene and (2R)-1,1,1-trifluoropropan-2-ol.

ESI-MS: m/z=224 (M+H)⁺, R_(t)(HPLC): 0.77 min (Z18_S04)

The following Intermediates are prepared in a similar manner tointermediate IV.1 by reduction from the corresponding startingmaterials:

ESI-MS Starting m/z Name material R M + H⁺ R_(t)(HPLC) IV.30 III.6

214 — IV.31 III.2

270 0.59 min (HPLC-H) IV.32 III.4

240 0.63 min (HPLC-M) IV.33 III.5

258 0.49 min (HPLC-A) IV.34 III.7

281 0.67 min (HPLC-A) IV.40 III.8

366 1.26 min (HPLC-M) IV.41 III.9

382 1.28 min (HPLC-M)

The following Intermediates are prepared according to the givenreferences:

Name R Reference IV.50

WO2011/104337 IV.51

WO2011/104334 IV.52

WO2011/104337 IV.53

WO2013/174744

Intermediate IV.60:

To 3.5 g (8.7 mmol)[(3R,3aR,6R,6aS)-3-[(3-nitro-2-pyridyl)oxy]-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]trifluoromethanesulfonate (prepared as described for III.3 from2-fluoro-3-nitro-pyridine and 1,4:3,6-dianhydro-D-mannitol) inacetonitrile 1.1 g (28.0 mmol) sodium borohydride are added. Thereaction mixture is stirred at RT for 4 days. The reaction mixture isevaporated, taken up in ice water, carefully acidified with aqueous 4 MHCl and extracted with EtOAc. The organic phases are pooled, washed withwater, dried and evaporated. The residue is purified by HPLC.

Yield: 0.2 g (11%), ESI-MS: m/z=223 (M+H)⁺, R_(t)(HPLC): 0.28 min(HPLC-G)

The following Intermediates are prepared according to the givenreferences:

Name Structure Reference V.1 

WO 2008/141843 V.3 

Adaptation of WO 2008/141843 V.4 

Adaptation of Org. Lett., 2004, 6(8), 1305-1307 V.5 

WO 2008/141843 V.8 

US2005/228027 V.9 

Adaptation of Org. Lett., 2004, 6(8), 1305-1307 V.10

WO2008/141843 V.11

Adaptation of WO2011/29537 V.15

Adaptation of Org. Lett., 2004, 6(8), 1305-1307 V.16

Org. Lett., 2004, 6(8), 1305-1307 V.17

Adaptation of Org. Lett., 2004, 6(8), 1305-1307 V.18

Adaptation of Org. Lett., 2004, 6(8), 1305-1307 V.19

Adaption of Tetrahedron, 1993, 49(37), 8449-8464

Intermediate VI.1:

Step 1:

A mixture of 1.6 g (4.24 mmol) intermediate IV.40 and 1.3 g (4.39 mmol)intermediate II.1 and glacial acetic acid are heated to 90° C. for 2.5h. After cooling to RT saturated NaHCO₃ solution is added followed byEtOAc. The aqueous phase is separated and extracted with EtOAc, theorganic phases are pooled and evaporated. A small amount of Et₂O isadded to the residual and the precipitate is filtered and dried givingrise to2-[(7-bromo-6-methoxy-5-methyl-quinazolin-4-yl)amino]-5-fluoro-phenol.

Yield: 1.2 g (75%), ESI-MS: m/z=378 (M+H)⁺, R_(t)(HPLC): 0.44 min(HPLC-G)

Step 2:

To a mixture of 1.2 g (3.17 mmol)2-[(7-bromo-6-methoxy-5-methyl-quinazolin-4-yl)amino]-5-fluoro-phenol0.8 g (6.35 mmol) (S)-2-Hydroxy-propionic acid ethyl ester, 2.5 g (9.53mmol) triphenylphosphine and THF at 0° C., 2.2 g (9.55 mmol)di-tertbutylazodicarboxylate in 20 ml THF is added. The reaction mixtureis warmed to RT and stirred for 2 h. The solvent is evaporated and theresidual is purified by FC yielding ethyl(2R)-2-[2-[(7-bromo-6-methoxy-5-methyl-quinazolin-4-yl)amino]-5-fluoro-phenoxy]propanoate.

Yield: 1.0 g (64%), ESI-MS: m/z=478 (M+H)⁺, R_(t)(HPLC): 0.57 min(HPLC-G)

Step 3:

To a mixture of 1.0 g (2.03 mmol) ethyl(2R)-2-[2-[(7-bromo-6-methoxy-5-methyl-quinazolin-4-yl)amino]-5-fluoro-phenoxy]propanoate,THF and EtOH, 5 ml (5.0 mmol) 1 M NaOH solution is added and thereaction mixture is stirred for 2 h at RT and neutralized with 1 M HCl.The precipitate is filtered and dried furnishing(2R)-2-[2-[(7-bromo-6-methoxy-5-methyl-quinazolin-4-yl)amino]-5-fluoro-phenoxy]propanoicacid.

Yield: 0.6 g (64%), ESI-MS: m/z=450 (M+H)⁺, R_(t)(HPLC): 0.71 min(HPLC-M)

Step 4:

To a mixture of 0.6 g (1.29 mmol(2R)-2-[2-[(7-bromo-6-methoxy-5-methyl-quinazolin-4-yl)amino]-5-fluoro-phenoxy]propanoicacid, 0.2 g (1.59 mmol 2,2,2-trifluoro-ethylamine, 0.6 ml (3.23 mmol)diisopropylethylamine and DMF, 0.5 g (1.42 mmol) HATU is added. Thereaction mixture is stirred at RT over night. The solvent is evaporatedand the residual is purified by FC yielding(2R)-2-[2-[(7-bromo-6-methoxy-5-methyl-quinazolin-4-yl)amino]-5-fluoro-phenoxy]-N-(2,2,2-trifluoroethyl)propanamide.

Yield: 0.5 g (69%), ESI-MS: m/z=531 (M+H)⁺, R_(t)(HPLC): 0.89 min(HPLC-A)

Intermediate VI.2:

Is prepared in similar manner as intermediate VI.1 using IV.41.

ESI-MS: m/z=547 (M+H)⁺, R_(t)(HPLC): 1.12 min (HPLC-M)

Intermediate VI.3:

Is prepared in similar manner as intermediate VI.1 using(2S)-1,1,1-trifluoropropan-2-amine.

ESI-MS: m/z=545 (M+H)⁺, R_(t)(HPLC): 1.11 min (HPLC-M)

Intermediate VI.4:

Step 1:

A mixture of 0.2 g (0.74 mmol) intermediate IV.2 and 0.3 g (0.74 mmol)intermediate II.3 and glacial acetic acid are heated to 80° C. for 2 hthen 90° C. for 24 h. After cooling to RT saturated NaHCO₃ solution isadded followed by DCM. The aqueous phase is separated and extracted withEtOAc, the organic phases are pooled and evaporated. MeOH and conc.NH₃-solution is added and the mixture is stirred at RT for 15 h, thenconcentrated. A small amount of MeOH is added to the residual and theprecipitate is filtered and dried giving rise7-bromo-4-[4-fluoro-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]anilino]-5-methyl-quinazolin-6-ol.

Yield: 0.4 g (Yield 50%), ESI-MS: m/z=460 (M+H)⁺, R_(t)(HPLC): 0.51 min(HPLC-W)

Step 2:

A mixture of 50 mg (0.11 mmol) intermediate VI.4 step 1, 20 mg (0.14mmol) 1-Bromo-2-chloro-ethane, 33 mg (0.24 mmol) K₂CO₃ and acetonitrileis heated to 80° C. in a sealed tube for 6 h. After cooling to RT thesolvent is evaporated and DCM and water are added. The organic phase isseparated, dried, filtered and evaporated giving rise to7-bromo-6-(2-chloroethoxy)-N-[4-fluoro-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]phenyl]-5-methyl-quinazolin-4-amine

Yield: 50 mg (Yield 88%), ESI-MS: m/z=522 M+H⁺, R_(t)(HPLC): 0.62 min(HPLC-W)

Step 3:

A mixture of 50 mg (0.10 mmol) intermediate VI.4 step 2, 14 mg (0.12mmol) 1-Methylpiperazin-2-one, 18 mg (0.13 mmol) K₂CO₃, 3 mg (0.02 mmol)NaI and acetonitrile is heated to 80° C. in a sealed tube for 7 h.Additional 14 mg (0.12 mmol) 1-Methylpiperazin-2-one and 18 mg (0.13mmol) K₂CO₃ are added and the mixture is heated to 100° C. in a sealedtube for 13 h. After cooling to RT the solvent is evaporated and DCM andwater are added. The organic phase is separated, dried, filtered andevaporated yielding4-[2-[7-bromo-4-[4-fluoro-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]anilino]-5-methyl-quinazolin-6-yl]oxyethyl]-1-methyl-piperazin-2-one.

Yield: 50 mg (Yield 87%), ESI-MS: m/z=600 M+H⁺, R_(t)(HPLC): 1.06 min(HPLC-M)

Intermediate VII.1:

Step 1:

A mixture of 0.7 g (3.05 mmol) intermediate IV.2 and 1.0 g (3.09 mmol)intermediate II.3 and glacial acetic acid are heated to 80° C. for 1.75h. After cooling to RT, the reaction mixture is concentrated andsaturated NaHCO₃ solution is added followed by DCM. The organic phase isseparated and concentrated and purified by FC giving rise to[7-bromo-4-[4-fluoro-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]anilino]-5-methyl-quinazolin-6-yl]acetate.

Yield: 1.3 g (Yield 85%), ESI-MS: m/z=502 (M+H)⁺, R_(t)(HPLC): 1.10 min(HPLC-M)

Step 2:

A mixture of 0.2 g (0.30 mmol) intermediate VII.1 step 1, 50 mg (0.54mmol) dimethylsulphoximine, 71 mg (0.09 mmol) Pd-PEPPSI-IPent Catalystand 0.5 g (1.54 mmol) Cs₂CO₃ and dioxane are heated in a sealed tube to65° C. for 2 h and to 100° C. over night. After cooling to RT thesolvent is evaporated and the crude product is purified by HPLC.

Yield: 30 mg (Yield 21%), ESI-MS: m/z=473 MH⁺, R_(t)(HPLC): 0.79 min(HPLC-M)

Methods of Preparation of Final Compounds

General Procedure 1 (P1) for Examples Shown in Table 1 and Table 2:

Equimolar amounts of the respective intermediates II and IV aredissolved in AcOH and heated to the given temperature for the giventime. The reaction mixture is diluted with water and saturated aqueousNaHCO₃-solution. An alternative workup comprises evaporation of thereaction mixture and treatment of the residue with MeOH and water. Incase the product precipitates it is filtered off, otherwise the mixtureis extracted with EtOAc. The organic phases are pooled dried andevaporated. If required, the crude product is further purified by FC orHPLC.

The following examples in table 1 (example number given in column #) areprepared according to P1, details are given in the column synthesiscomment, the retention-time and mass (ESI-MS m/z M+H⁺) determined byHPLC-MS are given in the columns MS and RT.

TABLE 1 Synthesis # Structure II IV MS RT Comment 1.01

II.5 IV.2 627 0.42 min HPLC-G 2 h 80° C. 1.02

II.6 IV.2 584 1.21 min HPLC-M 5 h 80° C. 1.03

II.7 IV.2 501 1.05 min HPLC-M 4 h 80° C. 1.04

II.8 IV.2 586 0.98 min HPLC-M 5 h 80° C.

General Procedure 2 (P2) for Examples Shown in Table 2:

A mixture of 1 eq of intermediate I, 1 eq of intermediate IV and Dioxaneis heated to 110° C. for 2 h then concentrated and diluted with water. 1eq NEt₃ or NH₃ is added and the mixture is stirred over night. Theprecipitate filtered off and dried, giving rise to the 7-hydroxyquinazoline to which 1.8 eq N-phenyltrifuoromethansulfonimide, 3 eqK₂CO₃ and THF are added and the mixture is stirred over night. Thereaction mixture is filtered and the filtrate concentrated giving riseto the aryl triflate.

General Procedure 3 (P3) for Examples Shown in Table 2:

1 eq of aryl bromide or aryl triflate, 1.2 eq sulphoximine and theamount of catalyst, ligand base and solvent given in the table Buchwaldconditions are heated to the given temperature for the given time. Thereaction mixture is concentrated and the crude product purified by HPLCor FC.

Table Buchwald conditions: Abbreviation Conditions BC1 0.1 eq Xanthphos0.1 eq PdOAc₂ 2.5 eq Cs₂CO₃ in Dioxane BC2 0.1 eq Xanthphos 0.1 eqPdOAc₂ 2.5 eq Cs₂CO₃ in Dioxane followed by deprotection with 10 eq TFAin DCM BC3 0.3 eq 2-(Di-t-butylphosphino) biphenyl 0.1 eq Pd₂dba₃ 2.0 eqNaOtBu in Dioxane BC4 0.3 eq 2-(Di-t-butylphosphino) biphenyl 0.1 eqPd₂dba₃ 2.3 eq Cs₂CO₃ in Dioxane BC5 0.2 eq BINAP 0.1 eq PdOAc₂ 1.4 eqCs₂CO₃ in Dioxane BC6 0.1 eq Xanthphos 0.1 eq PdOAc₂ 2.5 eq Cs₂CO₃ inDioxane followed by deprotection with pTsOH in MeOH BC7 0.2 eq2-(Di-t-butylphosphino) biphenyl 0.08 eq Pd₂dba₃ 1.5 eq NaOtBu inDioxane BC8 0.4 eq 2-(Di-t-butylphosphino) biphenyl 0.1 eq Pd₂dba₃ 2.3eq NaOtBu in Dioxane

To obtain the following examples shown in table 2 (example number givenin column #), the corresponding 7-bromo quinazoline (aryl bromide) isprepared according to P1 or quinazolin-7-yl trifluoromethanesulfonate(aryl triflate) is prepared according to P2 followed by couplingaccording to P3. Details are given in the column synthesis comment, theretention-time and mass (ESI-MS m/z M+H⁺) determined by HPLC-MS aregiven in the columns MS and RT.

TABLE 2 I/II Synthesis # Structure VI IV MS RT Comment 2.01

VI.1 — 586   0.97 min HPLC-M BC1 2.5 h  90° C. 2.02

I.1 IV.33 521.3 0.54 min HPLC-X BC1 1.5 h 100° C. 2.03

I.1 IV.32 529   0.74 min HPLC-V BC1 1 h 80° C. 2.04

I.1 IV.32 559.2 0.37 min HPLC-Q BC1 2 h 80° C. 2.05

VI.3 — 584   0.98 min HPLC-M BC8 2.75 h  80° C. 2.06

I.1 IV.1 531.2 0.56 min HPLC-N BC1 1.5 h  80° C. 2.07

II.1 IV.30 489   0.85 min HPLC-M BC3 2 h 80° C. 2.08

I.1 IV.32 543.3 0.57 min HPLC-X BC1 2 h 100° C. 2.09

II.1 IV.1 545.1 0.64 min HPLC-V BC3 2 h 80° C. 2.10

I.1 IV.60 512.2 0.48 min HPLC-K BC1 1.5 h 100° C. 2.11

VI.1 — 556   0.95 min HPLC-M BC3 2 h 80° C. 2.12

I.1 IV.32 573.3 0.53 min HPLC-Z BC1 2 h 100° C. 2.13

II.1 IV.1 519.1 0.61 min HPLC-V BC3 2 h 80° C. 2.14

I.1 IV.50 475   0.70 min HPLC-A BC1 1.5 h 100° C. 2.15

II.4 IV.2 612   1.03 min HPLC-M BC3 2.5 h  80° C. 2.16

I.1 IV.2 487.1 0.63 min HPLC-Z BC1 1.5 h  80° C. 2.17

I.1 IV.32 545.3 0.52 min HPLC-Z BC1 2 h 100° C. 2.18

I.2 IV.31 565   0.94 min HPLC-M BC1 1.5 h  80° C. 2.19

I.1 IV.32 545   0.54 min HPLC-U BC1 2 h 100° C. 2.20

II.1 IV.53 455   0.43 min HPLC-U BC7 3 h 100° C. 2.21

I.1 IV.60 498.2 0.47 min HPLC-K BC1 1.5 h 100° C. 2.22

II.1 IV.51 489   0.89 min HPLC-M BC4 4 h 90° C. 2.23

I.1 IV.32 533   0.42 min HPLC-U BC6 3 h 80° C. 2.24

VI.1 — 544.2 0.72 min HPLC-V BC3 2 h 80° C. 2.25

I.1 IV.32 503.2 0.47 min HPLC-K BC1 2 h 100° C. 2.26

I.1 IV.33 533.3 0.55 min HPLC-X BC1 1.5 h 100° C. 2.27

II.1 IV.53 467   0.45 min HPLC-U BC7 3 h 80° C. 2.28

I.2 IV.31 553   0.91 min HPLC-M BC1 1.5 h  80° C. 2.29

VI.2 — 560.1 0.78 min HPLC-V BC3 4.5 h  80° C. 2.30

I.1 IV.32 544.2 0.59 min HPLC-N BC2 2 h 100° C. 2.31

I.1 IV.32 531.3 0.55 min HPLC-Z BC1 2 h 100° C. 2.32

VI.4 — 613.3 0.77 min HPLC-T BC8 2.5 h  80° C. 2.33

I.2 IV.32 549.1 0.78 min HPLC-V BC1 1.5 h  80° C. 2.34

I.2 IV.50 495   0.73 min HPLC-A BC1 1.5 h  80° C. 2.35

I.1 IV.2 499.2 0.64 min HPLC-Z BC1 1.5 h  80° C. 2.36

I.1 IV.31 559   0.91 min HPLC-M BC1 1.5 h  80° C. 2.37

VI.3 — 558   0.95 min HPLC-M BC8 2.75 h  80° C. 2.38

II.1 IV.30 477.2 0.53 min HPLC-N BC3 2 h 80° C. 2.39

VI.2 — 572.1 0.81 min HPLC-V BC3 4.5 h  80° C. 2.40

I.2 IV.32 523   0.74 min HPLC-V BC1 1.5 h  80° C. 2.41

I.1 IV.31 545.2 0.63 min HPLC-N BC1 1.5 h  80° C. 2.42

I.1 IV.32 515.2 0.38 min HPLC-Q BC1 2 h 100° C. 2.43

I.1 IV.32 529.2 0.53 min HPLC-Z BC1 2 h 100° C. 2.44

II.1 IV.51 515   0.94 min HPLC-M BC5 3 h 100° C. 2.45

I.1 IV.31 533   0.68 min HPLC-V BC1 1.5 h  80° C. 2.46

II.1 IV.30 503   0.86 min HPLC-M BC3 2 h 80° C. 2.47

I.2 IV.34 564   0.85 min HPLC-A BC1 1.5 h  80° C. 2.48

I.1 IV.52 487   0.75 min HPLC-V BC1 1.5 h 100° C. 2.49

I.1 IV.60 486.2 0.45 min HPLC-K BC1 1.5 h 100° C. 2.50

I.1 IV.52 461   0.71 min HPLC-V BC1 1.5 h 100° C. 2.51

II.3 IV.2 473   0.99 min HPLC-M BC3 5.75 h  80° C. 2.52

VI.1 — 570.3 0.53 min HPLC-K BC3 2 h 80° C. 2.53

VI.3 — 570   0.97 min HPLC-M BC8 2.75 h  80° C. 2.54

I.1 IV.2 513   0.87 min HPLC-V BC1 1 h 80° C. 2.55

I.2 IV.31 579.1 0.76 min HPLC-V BC1 1.5 h  80° C. 2.56

VI.2 — 586.2 0.82 min HPLC-V BC3 4.5 h  80° C. 2.57

I.1 IV.52 473   0.74 min HPLC-V BC1 1.5 h 100° C. 2.58

II.1 IV.51 501   0.93 min HPLC-M BC3 2 h 80° C. 2.59

I.2 IV.32 535   0.77 min HPLC-V BC1 1.5 h  80° C.

General Procedure 4 (P4) for Examples Shown in Table 3:

A mixture of 1 eq of intermediate VII.1, 1.3 eq of alkylating agent and2.0 eq K₂CO₃ in DMF is stirred at the given temperature for the giventime. The reaction mixture is filtered and purified by HPLC.

To obtain the following examples (example number given in column #)shown in table 3, the corresponding compounds (example number given incolumn SM) are transformed according to P4. Details are given in thecolumn synthesis comment, the retention-time and mass (ESI-MS m/z M+H⁺)determined by HPLC-MS are given in the columns MS and RT.

TABLE 3 Synthesis # Structure VII SM MS RT Comment 3.01

VII.1 Bromo- methyl- cyclo- propane 527.1 0.92 min HPLC-V RT over night3.02

VII .1 1-Bromo-2- methoxy- ethane 531   1.02 min HPLC-M RT over night3.03

VII.1 2-Bromo- propane 515.1 0.91 min HPLC-V RT over night 3.04

VII.1 Tetrahydro- furan-3-yl tosylate 543   1.01 min HPLC-M RT overnight then 2.5 h 60° C.

The invention claimed is:
 1. A compound of formula (I)

wherein Ar is selected from the group consisting of:

wherein X is CH or N; R⁵ is H, halogen or CN; and R⁴ is selected fromthe group consisting of C₁₋₆-alkyl, C₃₋₇-cycloalkyl, heterocyclyl,—(CH₂)₁₋₃—C(═O)—NH—(C₁₋₅-alkyl) and —(CH₂)₁₋₃—C(═O)—N(CH₃)—(C₁₋₅-alkyl);wherein each alkyl or cycloalkyl group of R⁴ is optionally substitutedwith one or more F or one CN, OH or CF₃; wherein each heterocyclyl isoptionally substituted with one or more F and/or one OH or—O—(C₁₋₃-alkyl); or R⁴ is selected from the group consisting of:

R¹ is halogen, C₁₋₃-alkyl or —O—(C₁₋₃-alkyl); R² is selected from thegroup consisting of OH, —O—(C₁₋₆-alkyl), —O—(CH₂)₁₋₃—(C₃₋₇-cycloalkyl),—O—(CH₂)₁₋₃—O—(C₁₋₃-alkyl), —O-heterocyclyl and—O—(CH₂)₂₋₄-heterocyclyl, wherein in the definition of R², eachheterocyclyl is optionally substituted with one C₁₋₃-alkyl group, andwherein one CH₂ group of said heterocyclyl of R² may be replaced with acarbonyl group; R³ is selected from the group consisting of:

wherein R⁶ is C₁₋₂-alkyl; R⁷ is C₁₋₅-alkyl, C₃₋₇-cycloalkyl orheterocyclyl, wherein the alkyl group of R⁷ is optionally substitutedwith one or more F or with one OH or —O—(C₁₋₃-alkyl), and wherein theheterocyclyl group of R⁷ is tetrahydropyranyl; and or wherein R⁶ and R⁷together with the sulfur atom to which they are attached form a 4- to7-membered saturated or partly unsaturated heterocycle that may besubstituted in any position not adjacent to the sulfur atom by one ortwo F, OH or —O—(C₁₋₃-alkyl) or by one or two C₁₋₃-alkyl and thatfurther to the sulfur atom may contain one additional heteroatomselected from the group consisting of O, S and NR^(N), wherein R^(N) isH or C₁₋₃-alkyl, wherein, if not otherwise specified, each alkyl groupin the above definitions is linear or branched and may be substitutedwith one to three F; or a salt thereof.
 2. A compound of formula (I)according to claim 1, wherein R³ is selected from a group consisting of:

wherein R⁶ is CH₃; R⁷ is selected from the group consisting ofC₁₋₅-alkyl, cyclopropyl and tetrahydropyranyl, wherein the alkyl groupof R⁷ is optionally substituted with one OH or —O—CH₃, and or wherein R⁶and R⁷ together with the sulfur atom to which they are attached form a4- to 6-membered saturated heterocycle that may be substituted in anyposition not adjacent to the sulfur atom by one OH or —O—CH₃ or by oneor two CH₃ and that further to the sulfur atom may contain oneadditional heteroatom selected from the group consisting of O and NH; ora salt thereof.
 3. A compound of formula (I) according to claim 2,wherein R³ is selected from a group consisting of:

wherein R⁶ is CH₃; R⁷ is C₁₋₄-alkyl, cyclopropyl, —CH₂—CH₂—OH ortetrahydropyranyl; and Y is CH₂, CH(OH), O or NH; or a salt thereof. 4.A compound of formula (I) according to claim 1, wherein R¹ is CH₃ or Cl;and R² is selected from the group consisting of OH, —O—(C₁₋₄-alkyl),—O—CH₂-cyclopropyl, —O—(CH₂)₂—O—CH₃, —O— tetrahydrofuranyl and—O—(CH₂)₂₋₃-heterocyclyl, wherein each heterocyclyl is selected from agroup consisting of pyrrolidinyl, piperazinyl and morpholinyl, andwherein said piperazinyl group is optionally substituted with one CH₃group, and/or wherein one CH₂-group of said piperazinyl group may bereplaced with a carbonyl group, or a salt thereof.
 5. A compound offormula (I) according to claim 1, wherein Ar is:

wherein X is CH or N; R⁵ is H, F or Cl; and R⁴ is as defined in claim 1,or a salt thereof.
 6. A compound of formula (I) according to claim 1,wherein Ar is:

wherein R⁵ is F; and R⁴ is as defined in claim 1, or a salt thereof. 7.A compound of formula (I) according to claim 1, wherein R⁴ is selectedfrom the group consisting of: 1) C₁₋₄-alkyl optionally substituted withone to three F, 2) cyclohexyl optionally substituted with OH, 3) aheterocyclic group selected from:

wherein R¹⁰ is H, F, OH or —O—CH₃; and 4)—(CH₂)₁₋₃—C(═O)—NH—(C₁₋₄-alkyl), wherein the C₁₋₃-alkyl group linked tothe nitrogen atom is optionally substituted with one to three F, or asalt thereof.
 8. A compound of formula (I) according to claim 1, whereinR⁴ is selected from the group consisting of:

or a salt thereof.
 9. A compound of formula (I) according to claim 1,wherein Ar is selected from the group consisting of:

wherein X is CH or N; R⁵ is H, halogen or CN; and R⁴ is selected fromthe group consisting of C₁₋₆-alkyl, C₃₋₇-cycloalkyl, heterocyclyl,—(CH₂)₁₋₃—C(═O)—NH—(C₁₋₅-alkyl) and —(CH₂)₁₋₃—C(═O)—N(CH₃)—(C₁₋₅-alkyl);wherein each alkyl or cycloalkyl group of R⁴ is optionally substitutedwith one or more F or one CN, OH or CF₃; wherein in the definition ofR⁴, each heterocyclyl is selected from a group consisting oftetrahydrofuranyl, tetrahydropyranyl and

and is optionally substituted with F, OH or —O—(C₁₋₃-alkyl); R¹ is CH₃or Cl; R² is selected from the group consisting of OH, —O—(C₁₋₄-alkyl),—O—CH₂-cyclopropyl, —O—(CH₂)₁₋₃—O—CH₃, —O-tetrahydrofuranyl and—O—(CH₂)₂₋₃-heterocyclyl, wherein each heterocyclyl is selected from agroup consisting of pyrrolidinyl, piperazinyl and morpholinyl, eachoptionally substituted with one CH₃ group, and wherein one CH₂ group ofthe heterocyclyl group may be replaced with a carbonyl group; and R³ isselected from the group consisting of:

wherein R⁶ is CH₃; R⁷ is C₁₋₅-alkyl, cyclopropyl or tetrahydropyranyl,wherein the alkyl group of R⁷ is optionally substituted with one OH or—O—CH₃, and or wherein R⁶ and R⁷ together with the sulfur atom to whichthey are attached form a 4- to 6-membered saturated heterocycle that maybe substituted in any position not adjacent to the sulfur atom by one OHor —O—CH₃ and that further to the sulfur atom may contain one additionalheteroatom selected from the group consisting of 0 and NH; or apharmaceutically acceptable salt thereof.
 10. A compound of formula (I)according to claim 1, wherein Ar is selected from the group consistingof:

wherein R⁵ is F or Cl; and R⁴ is selected from the group consistingof: 1) C₁₋₄-alkyl optionally substituted with one to three F, 2)cyclohexyl optionally substituted with OH, 3) a heterocyclic groupselected from:

wherein R¹⁰ is H, F, OH or —O—CH₃; and 4)—(CH₂)₁₋₃—C(═O)—NH—(C₁₋₄-alkyl), wherein the C₁₋₃-alkyl group linked tothe nitrogen atom is optionally substituted with one to three F; R¹ isCH₃ or Cl; R² is selected from the group consisting of:

and R³ is selected from the group consisting of:

wherein R⁶ is CH₃; R⁷ is C₁₋₄-alkyl, cyclopropyl, —CH₂—CH₂—OH ortetrahydropyranyl; and Y is CH₂, CH(OH), O or NH; or a pharmaceuticallyacceptable salt thereof.
 11. A compound of formula (I) according toclaim 1 selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 12. A pharmaceuticallyacceptable salt of a compound according to claim
 1. 13. Pharmaceuticalcomposition comprising a compound according to claim 1 or apharmaceutically acceptable salt thereof and optionally apharmaceutically acceptable diluent or carrier.
 14. Pharmaceuticalcomposition according to claim 13 further comprising an additionaltherapeutic agent.
 15. Pharmaceutical composition according to claim 14wherein the additional therapeutic agent is selected from anantidiabetic agent, a lipid lowering agent, a cardiovascular agent, anantihypertensive agent, a diuretic agent, a thrombocyte aggregationinhibitor, an antineoplastic agent or an anti-obesity agent.
 16. Amethod of treating diabetes mellitus type 2, wherein said methodcomprises administration of a pharmaceutically active amount of acompound according to claim 1 or a pharmaceutically acceptable saltthereof to a patient in need thereof.
 17. The method according to claim16, wherein the method comprises concomitant or sequentialadministration to a patient in combination with an additionaltherapeutic agent.